Novel compounds

ABSTRACT

and salts thereof. The compounds of the invention are inhibitors of kinase activity, in particular PI3-kinase activity.

FIELD OF THE INVENTION

The present invention is directed to certain novel compounds which areinhibitors of kinase activity, processes for their preparation,pharmaceutical compositions comprising the compounds, and the use of thecompounds or the compositions in the treatment of various disorders.More specifically, the compounds of the invention are inhibitors of theactivity or function of the phosphoinositide 3′OH kinase family(hereinafter PI3-kinases), for example PI3Kδ, PI3Kα, PI3Kβ and/or PI3Kγ.Compounds which are inhibitors of the activity or function ofPI3-kinases may be useful in the treatment of disorders such asrespiratory diseases including asthma, chronic obstructive pulmonarydisease (COPD) and idiopathic pulmonary fibrosis (IPF); viral infectionsincluding viral respiratory tract infections and viral exacerbation ofrespiratory diseases such as asthma and COPD; non-viral respiratoryinfections including aspergillosis and leishmaniasis; allergic diseasesincluding allergic rhinitis and atopic dermatitis; autoimmune diseasesincluding rheumatoid arthritis and multiple sclerosis; inflammatorydisorders including inflammatory bowel disease; cardiovascular diseasesincluding thrombosis and atherosclerosis; hematologic malignancies;neurodegenerative diseases; pancreatitis; multiorgan failure; kidneydiseases; platelet aggregation; cancer; sperm motility; transplantationrejection; graft rejection; lung injuries; and pain including painassociated with rheumatoid arthritis or osteoarthritis, back pain,general inflammatory pain, post hepatic neuralgia, diabetic neuropathy,inflammatory neuropathic pain (trauma), trigeminal neuralgia and Centralpain.

BACKGROUND OF THE INVENTION

Cellular membranes represent a large store of second messengers that canbe enlisted in a variety of signal transduction pathways. In relation tofunction and regulation of effector enzymes in phospholipids signalingpathways, class I PI3-kinases (e.g. PI3Kdelta) generate secondmessengers from the membrane phospholipid pools. Class I PI3Ks convertthe membrane phospholipid PI(4,5)P₂ into PI(3,4,5)P₃, which functions asa second messenger. PI and PI(4)P are also substrates of PI3K and can bephosphorylated and converted into PI3P and PI(3,4)P₂, respectively. Inaddition, these phosphoinositides can be converted into otherphosphoinositides by 5′-specific and 3′-specific phophatases. Thus, PI3Kenzymatic activity results either directly or indirectly in thegeneration of two 3′-phosphoinositide subtypes which function as secondmessengers in intracellular signal transduction pathways (TrendsBiochem. Sci. 22(7) p. 267-72 (1997) by Vanhaesebroeck et al.; Chem.Rev. 101(8) p. 2365-80 (2001) by Leslie et al.; Annu. Rev. Cell Dev.Biol. 17 p. 615-75 (2001) by Katso et al.; and Cell. Mol. Life Sci.59(5) p. 761-79 (2002) by Toker). To date, eight mammalian PI3Ks havebeen identified, divided into three main classes (I, II, and III) on thebasis of sequence homology, structure, binding partners, mode ofactivation, and substrate preference. In vitro, class I PI3Ks canphosphorylate phosphatidylinositol (PI),phosphatidylinositol-4-phosphate (PI4P), andphosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂) to producephosphatidylinositol-3-phosphate (PI3P),phosphatidylinositol-3,4-bisphosphate (PI(3,4)P₂, andphosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P₃, respectively.Class II PI3Ks can phosphorylate PI and PI4P. Class III PI3Ks can onlyphosphorylate PI (Vanhaesebroeck et al. (1997), above; Vanhaesebroeck etal. Exp. Cell Res. 253(1) p. 239-54 (1999); and Leslie et al. (2001),above).

Class I PI3K is a heterodimer consisting of a p110 catalytic subunit anda regulatory subunit, and the family is further divided into class Iaand class Ib enzymes on the basis of regulatory partners and mechanismof regulation. Class Ia enzymes consist of three distinct catalyticsubunits (p110α, p110β, and p110δ) that dimerise with five distinctregulatory subunits (p85α, p55α, p50α, p85β, and p55γ), with allcatalytic subunits being able to interact with all regulatory subunitsto form a variety of heterodimers. Class Ia PI3K are generally activatedin response to growth factor-stimulation of receptor tyrosine kinases,via interaction of the regulatory subunit SH2 domains with specificphospho-tyrosine residues of the activated receptor or adaptor proteinssuch as IRS-1. Small GTPases (ras as an example) are also involved inthe activation of PI3K in conjunction with receptor tyrosine kinaseactivation. Both p110α and p110 are constitutively expressed in all celltypes, whereas p110δ expression is more restricted to leukocytepopulations and some epithelial cells. In contrast, the single Class Ibenzyme consists of a p110γ catalytic subunit that interacts with a p101regulatory subunit. Furthermore, the Class Ib enzyme is activated inresponse to G-protein coupled receptor (GPCR) systems and its expressionappears to be limited to leukocytes.

As illustrated in Scheme A above, phosphoinositide 3-kinases (PI3Ks)phosphorylate the hydroxyl of the third carbon of the inositol ring. Thephosphorylation of phosphoinositides to generate PtdIns(3,4,5)P₃,PtdIns(3,4)P₂ and PtdIns(3)P, produces second messengers for a varietyof signal transduction pathways, including those essential to cellproliferation, cell differentiation, cell growth, cell size, cellsurvival, apoptosis, adhesion, cell motility, cell migration,chemotaxis, invasion, cytoskeletal rearrangement, cell shape changes,vesicle trafficking and metabolic pathway (Katso et al. (2001), above;and Mol. Med. Today 6(9) p. 347-57 (2000) by Stein et al.).

The activity of PI3-kinases responsible for generating thesephosphorylated signalling products was originally identified as beingassociated with viral oncoproteins and growth factor receptor tyrosinekinases that phosphorylate phosphatidylinositol (PI) and itsphosphorylated derivatives at the 3′-hydroxyl of the inositol ring(Panayotou et al. Trends Cell Biol. 2 p. 358-60 (1992)). However, morerecent biochemical studies have revealed that class I PI3-kinases (e.g.class IA isoform PI3Kδ) are dual-specific kinase enzymes, meaning theydisplay both lipid kinase (phosphorylation of phosphoinositides) as wellas protein kinase activity, which have been shown to be capable ofphosphorylation of other protein as substrates, includingauto-phosphorylation as an intramolecular regulatory mechanism (EMBO J.18(5) p. 1292-302 (1999) by Vanhaesebroeck et al.). Cellular processesin which PI3Ks play an essential role include suppression of apoptosis,reorganization of the actin skeleton, cardiac myocyte growth, glycogensynthase stimulation by insulin, TNFα-mediated neutrophil priming andsuperoxide generation, and leukocyte migration and adhesion toendothelial cells.

PI3-kinase activation, is believed to be involved in a wide range ofcellular responses including cell growth, differentiation, and apoptosis(Parker, Current Biology 5(6) p. 577-79 (1995); and Yao et al. Science267(5206) p. 2003-06 (1995)). PI3-kinase appears to be involved in anumber of aspects of leukocyte activation. A p85-associated PI3-kinasehas been shown to physically associate with the cytoplasmic domain ofCD28, which is an important costimulatory molecule for the activation ofT-cells in response to antigen (Pages et al. Nature 369 p. 327-29(1994); and Rudd, Immunity 4 p. 527-34 (1996)). Activation of T cellsthrough CD28 lowers the threshold for activation by antigen andincreases the magnitude and duration of the proliferative response.These effects are linked to increases in the transcription of a numberof genes including interleukin-2 (IL2), an important T cell growthfactor (Fraser et al. Science 251(4991) p. 313-16 (1991)).

PI3Kγ has been identified as a mediator of G beta-gamma-dependentregulation of JNK activity, and G beta-gamma are subunits ofheterotrimeric G proteins (Lopez-Ilasaca et al. J. Biol. Chem. 273(5) p.2505-8 (1998)). Recently, (Laffargue et al. Immunity 16(3) p. 441-51(2002)) it has been described that PI3Kγ relays inflammatory signalsthrough various G(i)-coupled receptors and is central to mast cellfunction, stimuli in the context of leukocytes, and immunology includingcytokines, chemokines, adenosines, antibodies, integrins, aggregationfactors, growth factors, viruses or hormones for example (J. Cell Sci.114 (Pt 16) p. 2903-10 (2001) by Lawlor et al.; Laffargue et al. (2002),above; and Curr. Opinion Cell Biol. 14(2) p. 203-13 (2002) by Stephenset al.).

Specific inhibitors against individual members of a family of enzymesprovide invaluable tools for deciphering functions of each enzyme. Twocompounds, LY294002 and wortmannin (hereinafter), have been widely usedas PI3-kinase inhibitors. These compounds are non-specific PI3Kinhibitors, as they do not distinguish among the four members of Class IPI3-kinases. For example, the IC₅₀ values of wortmannin against each ofthe various Class I PI3-kinases are in the range of 1-10 nM. Similarly,the IC₅₀ values for LY294002 against each of these PI3-kinases is about15-20 μM (Fruman et al. Ann. Rev. Biochem. 67 p. 481-507 (1998)), also5-10 microM on CK2 protein kinase and some inhibitory activity onphospholipases. Wortmannin is a fungal metabolite which irreversiblyinhibits PI3K activity by binding covalently to the catalytic domain ofthis enzyme. Inhibition of PI3K activity by wortmannin eliminatessubsequent cellular response to the extracellular factor. For example,neutrophils respond to the chemokine fMet-Leu-Phe (fMLP) by stimulatingPI3K and synthesizing PtdIns (3, 4, 5)P₃. This synthesis correlates withactivation of the respiratory burst involved in neutrophil destructionof invading microorganisms. Treatment of neutrophils with wortmanninprevents the fMLP-induced respiratory burst response (Thelen et al.Proc. Natl. Acad. Sci. USA 91 p. 4960-64 (1994)). Indeed, theseexperiments with wortmannin, as well as other experimental evidence,show that PI3K activity in cells of hematopoietic lineage, particularlyneutrophils, monocytes, and other types of leukocytes, is involved inmany of the non-memory immune response associated with acute and chronicinflammation.

Based on studies using wortmannin, there is evidence that PI3-kinasefunction is also required for some aspects of leukocyte signalingthrough G-protein coupled receptors (Thelen et al. (1994), above).Moreover, it has been shown that wortmannin and LY294002 blockneutrophil migration and superoxide release.

It is now well understood that deregulation of oncogenes and tumoursuppressor genes contributes to the formation of malignant tumours, forexample by way of increased cell growth and proliferation or increasedcell survival. It is also now known that signaling pathways mediated bythe PI3K family have a central role in a number of cell processesincluding proliferation and survival, and deregulation of these pathwaysis a causative factor a wide spectrum of human cancers and otherdiseases (Katso et al. Annual Rev. Cell Dev. Biol. (2001) 17 p. 615-675and Foster et al. J. Cell Science (2003) 116(15) p. 3037-3040). PI3Keffector proteins initiate signalling pathways and networks bytranslocating to the plasma membrane through a conserved PleckstrinHomology (PH) domain, which specifically interacts with PtdIns(3,4,5)P3(Vanhaesebroeck et al. Annu. Rev. Biochem. (2001) 70 p. 535-602). Theeffector proteins signalling through PtdIns(3,4,5)P3 and PH domainsinclude Serine/Threonine (Ser/Thr) kinases, Tyrosine kinases, Rac or ArfGEFs (Guanine nucleotide exchange factors) and Arf GAPs (GTPaseactivating proteins).

In B and T cells PI3Ks have an important role through activation of theTec family of protein tyrosine kinases which include Bruton's tyrosinekinase (BTK) in B cells and Interleukin-2-inducible T-cell kinase (ITK)in T cells. Upon PI3K activation, BTK or ITK translocate to the plasmamembrane where they are subsequently phosphorylated by Src kinases. Oneof the major targets of activated ITK is phospholipase C-gamma (PLCγ1),which hydrolyses PtdIns(4,5)P2 into Ins(3,4,5)P3 and initiates anintracellular increase in calcium levels and diacylglycerol (DAG) whichcan activate Protein Kinases C in activated T cells.

Unlike the Class IA p110α and p110β, p110δ is expressed in a tissuerestricted fashion.

Its high expression level in lymphocytes and lymphoid tissues suggests arole in PI3K-mediated signalling in the immune system. The p110δ kinasedead knock-in mice are also viable and their phenotype is restricted todefects in immune signalling (Okkenhaug et al. Science (2002) 297 p.1031-4). These transgenic mice have offered insight into the function ofPI3Kδ in B-cell and T-cell signalling. In particular, p110δ is requiredfor PtdIns(3,4,5)P3 formation downstream of CD28 and/or T cell Receptor(TCR) signalling. A key effect of PI3K signalling downstream of TCR isthe activation of Akt, which phosphorylates anti-apoptotic factors aswell as various transcription factors for cytokine production. As aconsequence, T cells with inactive p110δ have defects in proliferationand Th1 and Th2 cytokine secretion. Activation of T cells through CD28lowers the threshold for TCR activation by antigen and increases themagnitude and duration of the proliferative response. These effects aremediated by the PI3Kδ-dependent increase in the transcription of anumber of genes including IL2, an important T cell growth factor.

Therefore, PI3K inhibitors are anticipated to provide therapeuticbenefit via its role in modulating T-cell mediated inflammatoryresponses associated to respiratory diseases such as asthma, COPD andcystic fibrosis. In addition, there is indication that T-cell directedtherapies may provide corticosteroid sparing properties (Alexander etal. Lancet (1992) 339 p. 324-8) suggesting that it may provide a usefultherapy either as a standalone or in combination with inhaled or oralglucocorticosteroids in respiratory diseases. A PI3K inhibitor mightalso be used alongside other conventional therapies such as a longacting beta-agonists (LABA) in asthma.

In the vasculature, PI3Kδ is expressed by endothelial cells andparticipates in neutrophil trafficking by modulating the proadhesivestate of these cells in response to TNFalpha (Puri et al. Blood (2004)103(9) p. 3448-56.). A role for PI3Kδ in TNFalpha-induced signalling ofendothelial cells is demonstrated by the pharmacological inhibition ofAkt phosphorylation and PDK1 activity. In addition, PI3Kδ is implicatedin vascular permeability and airway tissue edema through the VEGFpathway (Lee et al. J. Allergy Clin. Immunol. (2006) 118(2) p. 403-9).These observations suggest additional benefits of PI3Kδ inhibition inasthma by the combined reduction of leukocyte extravasation and vascularpermeability associated with asthma. In addition, PI3Kδ activity isrequired for mast cell function both in vitro and in vivo (Ali et al.Nature (2004) 431 p. 1007-11; and Ali et al. J. Immunol. (2008) 180(4)p. 2538-44) further suggesting that PI3K inhibition should be oftherapeutical benefit for allergic indications such asthma, allergicrhinitis and atopic dermatitis.

The role of PI3Kδ in B cell proliferation, antibody secretion, B-cellantigen and IL-4 receptor signalling, B-cell antigen presenting functionis also well established Okkenhaug et al. (2002), above; Al-Alwan et al.J. Immunol. (2007) 178(4) p. 2328-35; and Bilancio et al. Blood (2006)107(2) p. 642-50) and indicates a role in autoimmune diseases such asrheumatoid arthritis or systemic lupus erythematosus. Therefore PI3Kinhibitors may also be of benefit for these indications.

Pharmacological inhibition of PI3Kδ inhibits fMLP-dependent neutrophilchemotaxis on an ICAM coated agarose matrix integrin-dependent biasedsystem (Sadhu et al., J. Immunol. (2003) 170(5) p. 2647-54.). Inhibitionof PI3Kδ regulates neutrophil activation, adhesion and migration withoutaffecting neutrophil mediated phagocytosis and bactericidal activityover Staphylococcus aureus (Sadhu et al. Biochem. Biophys. Res. Commun.(2003) 308(4) p. 764-9). Overall, the data suggest that PI3Kδ inhibitionshould not globally inhibit neutrophil functions required for innateimmune defence. PI3Kδ's role in neutrophils offers further scope fortreating inflammatory diseases involving tissue remodeling such as COPDor rheumatoid arthritis.

In addition, there is also good evidence that class Ia PI3K enzymes alsocontribute to tumourigenesis in a wide variety of human cancers, eitherdirectly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer(2002) 2(7) p. 489-501). For example, inhibition of PI3Kδ may have atherapeutic role for the treatment of malignant haematological disorderssuch as acute myeloid leukaemia (Billottet et al. Oncogene (2006) 25(50)p. 6648-59). Moreover, activating mutations within p110α (PIK3CA gene)have been associated with various other tumors such as those of thecolon and of the breast and lung (Samuels et al. Science (2004)304(5670) p. 554).

It has also been shown that PI3K is involved in the establishment ofcentral sensitization in painful inflammatory conditions (Pezet et al.The J. of Neuroscience (2008) 28 (16) p. 4261-4270).

A wide variety of retroviruses and DNA based viruses activate the PI3Kpathway as a way of preventing host cell death during viral infectionand ultimately exploiting the host cell synthesis machinery for itsreplication (Virology 344(1) p. 131-8 (2006) by Vogt et al.; and Nat.Rev. Microbiol. 6(4) p. 265-75 (2008) by Buchkovich et al.). ThereforePI3K inhibitors may have anti-viral properties in addition to moreestablished oncolytic and anti-inflammatory indications. These antiviraleffects raise interesting prospects in viral induced inflammatoryexacerbations. For example, the common cold human rhinovirus (HRV) isresponsible for more than 50% of respiratory tract infections butcomplications of these infections can be significant in certainpopulations. This is particularly the case in respiratory diseases suchas asthma or chronic obstruction pulmonary disease (COPD). Rhinoviralinfection of epithelial cells leads to a PI3K dependent cytokine andchemokine secretion (J. Biol. Chem. (2005) 280(44) p. 36952 by Newcombet al.). This inflammatory response correlates with worsening ofrespiratory symptoms during infection. Therefore PI3K inhibitors maydampen an exaggerated immune response to an otherwise benign virus. Themajority of HRV strains infect bronchial epithelial cells by initiallybinding to the ICAM-1 receptor. The HRV-ICAM-1 complex is then furtherinternalised by endocytosis and it has been shown that this eventrequires PI3K activity (J. Immunol. (2008) 180(2) p. 870-880 by Lau etal.). Therefore, PI3K inhibitors may also block viral infections byinhibiting viral entry into host cells.

PI3K inhibitors may be useful in reducing other types of respiratoryinfections including the fungal infection aspergillosis (MucosalImmunol. (2010) 3(2) p. 193-205 by Bonifazi et al.). In addition, PI3Kδdeficient mice are more resistant towards infections by the protozoanparasite Leishmania major (J. Immunol. (2009) 183(3) p. 1921-1933 by Liuet al.). Taken with effects on viral infections, these reports suggestthat PI3K inhibitors may be useful for the treatment of a wide varietyof infections.

PI3K inhibition has also been shown to promote regulatory T celldifferentiation (Proc. Natl. Acad. Sci. USA (2008) 105(22) p. 7797-7802by Sauer et al.) suggesting that PI3K inhibitors may serve therapeuticpurposes in auto-immune or allergic indications by inducingimmuno-tolerance towards self antigen or allergen. Recently the PI3Kδisoform has also been linked to smoke induced glucocorticoidinsensitivity (Am. J. Respir. Crit. Care Med. (2009) 179(7) p. 542-548by Marwick et al.). This observation suggests that COPD patients, whichotherwise respond poorly to corticosteroids, may benefit from thecombination of a PI3K inhibitor with a corticosteroid.

PI3K has also been involved in other respiratory conditions such asidiopathic pulmonary fibrosis (IPF). IPF is a fibrotic disease withprogressive decline of lung function and increased mortality due torespiratory failure. In IPF, circulating fibrocytes are directed to thelung via the chemokine receptor CXCR4. PI3K is required for bothsignalling and expression of CXCR4 (Int. J. Biochem. and Cell Biol.(2009) 41 p. 1708-1718 by Mehrad et al.). Therefore, by reducing CXCR4expression and blocking its effector function, a PI3K inhibitor shouldinhibit the recruitment of fibrocytes to the lung and consequently slowdown the fibrotic process underlying IPF, a disease with high unmetneed.

Attempts have been made to prepare compounds which inhibit PI3-kinaseactivity and a number of such compounds have been disclosed in the art.However, in view of the number of pathological responses which aremediated by PI3-kinases, there remains a continuing need for inhibitorsof PI3-kinase which can be used in the treatment of a variety ofconditions.

The present inventors have discovered novel compounds which areinhibitors of kinase activity, in particular PI3-kinase activity.Compounds which are PI3-kinase inhibitors may be useful in the treatmentof disorders associated with inappropriate kinase activity, inparticular inappropriate PI3-kinase activity, for example in thetreatment and prevention of disorders mediated by PI3-kinase mechanisms.Such disorders include respiratory diseases including asthma, chronicobstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis(IPF); viral infections including viral respiratory tract infections andviral exacerbation of respiratory diseases such as asthma and COPD;non-viral respiratory infections including aspergillosis andleishmaniasis; allergic diseases including allergic rhinitis and atopicdermatitis; autoimmune diseases including rheumatoid arthritis andmultiple sclerosis; inflammatory disorders including inflammatory boweldisease; cardiovascular diseases including thrombosis andatherosclerosis; hematologic malignancies; neurodegenerative diseases;pancreatitis; multiorgan failure; kidney diseases; platelet aggregation;cancer; sperm motility; transplantation rejection; graft rejection; lunginjuries; and pain including pain associated with rheumatoid arthritisor osteoarthritis, back pain, general inflammatory pain, post hepaticneuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma),trigeminal neuralgia and Central pain.

In one embodiment, compounds of the invention may show selectivity forPI3-kinases over other kinases.

In another embodiment, compounds of the invention may be potentinhibitors of PI3Kδ.

In a further embodiment, compounds of the invention may show selectivityfor PI3Kδ over other PI3-kinases.

SUMMARY OF THE INVENTION

The invention is directed to certain novel compounds. Specifically, theinvention is directed to compounds of formula (I)

wherein R¹, R², R³ and R⁴ are as defined below, and salts thereof.

The compounds are inhibitors of kinase activity, in particularPI3-kinase activity. Compounds which are PI3-kinase inhibitors may beuseful in the treatment of disorders associated with inappropriatePI3-kinase activity, such as asthma and chronic obstructive pulmonarydisease (COPD). Accordingly, the invention is further directed topharmaceutical compositions comprising a compound of formula (I) or apharmaceutically acceptable salt thereof. The invention is still furtherdirected to methods of inhibiting PI3-kinase activity and treatment ofdisorders associated therewith using a compound of formula (I) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. The invention is yet further directed towardsprocesses for the preparation of the compounds of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the X-ray powder diffraction (XRPD) data for Example 10.

FIG. 2 shows the X-ray powder diffraction (XRPD) data for Example 1.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention is directed to compounds of formula (I)

wherein

R¹ is 9- or 10-membered bicyclic heteroaryl wherein the 9- or10-membered bicyclic heteroaryl contains from one to three heteroatomsindependently selected from oxygen and nitrogen and is optionallysubstituted by C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, —CN or —NHSO₂R⁵, or

pyridinyl optionally substituted by one or two substituentsindependently selected from C₁₋₆ alkyl, —OR⁶, halo and —NHSO₂R⁷;

R² and R³, together with the nitrogen atom to which they are attached,are linked to form a 6- or 7-membered heterocyclyl wherein the 6- or7-membered heterocyclyl optionally contains an oxygen atom or a furthernitrogen atom and is optionally substituted by one or two substituentsindependently selected from C₁₋₆alkyl;

R⁴ is hydrogen or methyl;

R⁶ is hydrogen or C₁₋₄alkyl; and

R⁵ and R⁷ are each independently C₁₋₆alkyl, or phenyl optionallysubstituted by one or two substituents independently selected from halo;

and salts thereof (hereinafter “compounds of the invention”).

In one embodiment, R¹ is 9-membered bicyclic heteroaryl wherein the9-membered bicyclic heteroaryl contains one or two nitrogen atoms, orpyridinyl optionally substituted by one or two substituentsindependently selected from —OR⁶ and —NHSO₂R⁷. In another embodiment, R¹is 9- or 10-membered bicyclic heteroaryl wherein the 9- or 10-memberedbicyclic heteroaryl contains from one to three heteroatoms independentlyselected from oxygen and nitrogen and is optionally substituted byC₁₋₆alkyl, C₃₋₆cycloalkyl, halo, —CN or —NHSO₂R⁵. In another embodiment,R¹ is 9- or 10-membered bicyclic heteroaryl wherein the 9- or10-membered bicyclic heteroaryl contains one or two nitrogen atoms andis optionally substituted by C₁₋₆alkyl or halo. In another embodiment,R¹ is 9-membered bicyclic heteroaryl wherein the 9-membered bicyclicheteroaryl contains one or two nitrogen atoms. In another embodiment, R¹is indolyl, for example 1H-indol-4-yl. In another embodiment, R¹ ispyridinyl optionally substituted by one or two substituentsindependently selected from C₁₋₆alkyl, —OR⁶, halo and —NHSO₂R⁷. Inanother embodiment, R¹ is pyridinyl optionally substituted by one or twosubstituents independently selected from —OR⁶ and —NHSO₂R⁷. In a furtherembodiment, R¹ is pyridinyl substituted by —OR⁶ and —NHSO₂R⁷.

In one embodiment, R² and R³, together with the nitrogen atom to whichthey are attached, are linked to form a 6-membered heterocyclyl whereinthe 6-membered heterocyclyl optionally contains an oxygen atom or afurther nitrogen atom and is optionally substituted by one or twosubstituents independently selected from C₁₋₆alkyl. In anotherembodiment, R² and R³, together with the nitrogen atom to which they areattached, are linked to form a 6-membered heterocyclyl wherein the6-membered heterocyclyl optionally contains an oxygen atom or a furthernitrogen atom and is substituted by one or two substituentsindependently selected from C₁₋₄alkyl, for example methyl. In anotherembodiment, R² and R³, together with the nitrogen atom to which they areattached, are linked to form a 6-membered heterocyclyl wherein the6-membered heterocyclyl contains an oxygen atom and is optionallysubstituted by one or two substituents independently selected fromC₁₋₄alkyl, for example methyl. In another embodiment, R² and R³,together with the nitrogen atom to which they are attached, are linkedto form a 6-membered heterocyclyl wherein the 6-membered heterocyclylcontains an oxygen atom and is substituted by one or two substituentsindependently selected from C₁₋₆alkyl. In another embodiment, R² and R³,together with the nitrogen atom to which they are attached, are linkedto form a 6-membered heterocyclyl wherein the 6-membered heterocyclylcontains a further nitrogen atom and is optionally substituted byC₁₋₄alkyl, for example isopropyl. In a further embodiment, R² and R³,together with the nitrogen atom to which they are attached, are linkedto form a 6-membered heterocyclyl wherein the 6-membered heterocyclylcontains a further nitrogen atom and is substituted by C₁₋₄alkyl, forexample isopropyl.

In one embodiment, R⁴ is hydrogen.

In one embodiment, R⁵ is C₁₋₄alkyl such as methyl.

In one embodiment, R⁶ is C₁₋₄alkyl such as methyl.

In one embodiment, R⁷ is C₁₋₆alkyl. In another embodiment, R⁷ isC₁₋₄alkyl such as methyl. In a further embodiment, R⁷ is phenyloptionally substituted by one or two substituents independently selectedfrom halo, for example fluoro.

It is to be understood that the present invention covers allcombinations of substituent groups described hereinabove.

In one embodiment, the invention is directed to compounds of formula(IA)

wherein

R¹ is pyridinyl optionally substituted by one or two substituentsindependently selected from —OR⁶ and —NHSO₂R⁷;

R² and R³, together with the nitrogen atom to which they are attached,are linked to form a 6-membered heterocyclyl wherein the 6-memberedheterocyclyl contains an oxygen atom and is optionally substituted byone or two substituents independently selected from C₁₋₄ alkyl;

R⁴ is hydrogen;

R⁶ is C₁₋₄alkyl; and

R⁷ is C₁₋₄alkyl;

and salts thereof.

In a further embodiment, the invention is directed to compounds offormula (IB)

wherein

R¹ is indolyl;

R² and R³, together with the nitrogen atom to which they are attached,are linked to form a 6-membered heterocyclyl wherein the 6-memberedheterocyclyl contains a further nitrogen atom and is optionallysubstituted by C₁₋₄alkyl; and

R⁴ is hydrogen;

and salts thereof.

Compounds of the invention include the compounds of Examples 1 to 9 andsalts thereof.

In one embodiment, the compound of the invention is:

-   N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide;-   N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide;-   N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide;-   2,4-difluoro-N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide;-   4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-6-(1H-indol-4-yl)-1H-indazole;-   6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole;-   6-(1H-indol-4-yl)-4-[5-(4-morpholinylmethyl)-1,3-oxazol-2-yl]-1H-indazole;-   N-[5-[4-(5-{[(2R,6R)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide;-   6-(1H-indol-4-yl)-4-[5-(1-piperazinylmethyl)-1,3-oxazol-2-yl]-1H-indazole;

or a salt thereof.

In another embodiment, the compound of the invention is:

-   N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide;-   N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide;-   N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide;-   2,4-difluoro-N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide;-   4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-6-(1H-indol-4-yl)-1H-indazole;-   6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole;-   6-(1H-indol-4-yl)-4-[5-(4-morpholinylmethyl)-1,3-oxazol-2-yl]-1H-indazole;

or a salt thereof.

In another embodiment, the compound of the invention is:

-   N-[5-[4-(5-{[2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide;

or a salt thereof.

In another embodiment, the compound of the invention is:

-   N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide;

or a salt thereof.

In another embodiment, the compound of the invention is:

-   N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide    (R)-mandelate.

In another embodiment, the compound of the invention is:

-   N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide.

In another embodiment, the compound of the invention is:

-   6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole;

or a salt thereof.

In another embodiment, the compound of the invention is:

-   6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole    hydrochloride.

In a futher embodiment, the compound of the invention is:

-   6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole.

Terms and Definitions

“Alkyl” refers to a saturated hydrocarbon chain having the specifiednumber of member atoms. For example, C₁₋₆alkyl refers to an alkyl grouphaving from 1 to 6 member atoms, for example 1 to 4 member atoms. Alkylgroups may be straight or branched.

Representative branched alkyl groups have one, two, or three branches.Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl(n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, andneopentyl), and hexyl.

“Cycloalkyl” refers to a saturated hydrocarbon ring having the specifiednumber of member atoms. Cycloalkyl groups are monocyclic ring systems.For example, C₃₋₆cycloalkyl refers to a cycloalkyl group having from 3to 6 member atoms. In one embodiment, the cycloalkyl groups have 3 or 4member atoms. In a further embodiment, the cycloalkyl groups have 5 or 6member atoms. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,and cyclohexyl.

“Enantiomerically enriched” refers to products whose enantiomeric excessis greater than zero. For example, enantiomerically enriched refers toproducts whose enantiomeric excess is greater than 50% ee, greater than75% ee, and greater than 90% ee.

“Enantiomeric excess” or “ee” is the excess of one enantiomer over theother expressed as a percentage. As a result, since both enantiomers arepresent in equal amounts in a racemic mixture, the enantiomeric excessis zero (0% ee). However, if one enantiomer was enriched such that itconstitutes 95% of the product, then the enantiomeric excess would be90% ee (the amount of the enriched enantiomer, 95%, minus the amount ofthe other enantiomer, 5%).

“Enantiomerically pure” refers to products whose enantiomeric excess is99% ee or greater.

“Half-life” (or “half-lives”) refers to the time required for half of aquantity of a substance to be converted to another chemically distinctspecies in vitro or in vivo.

“Halo” refers to the halogen radical fluoro, chloro, bromo, or iodo.

“Heteroaryl”, unless otherwise defined, refers to an aromatic groupcontaining from 1 to 3 heteroatoms as member atoms. Heteroaryl groupscontaining more than one heteroatom may contain different heteroatoms.Heteroaryl groups may be optionally substituted as defined herein. Theheteroaryl groups herein are fused bicyclic ring systems. The bicyclicheteroaryl rings have 9 or 10 member atoms. Bicyclic heteroaryl includesindolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl,indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl,pyrrolopyrimidinyl, quinolyl, isoquinolinyl, quinoxalinyl, quinazolinyl,cinnolinyl, benzopyranyl, benzoxazolyl, furopyridinyl and naphthridinyl.

“Heteroatom” refers to a nitrogen, sulphur, or oxygen atom.

“Heterocyclyl”, unless otherwise defined, refers to a saturated orunsaturated ring containing 1 or 2 heteroatoms as member atoms in thering. However, heterocyclyl rings are not aromatic. In certainembodiments, heterocyclyl is saturated. In other embodiments,heterocyclyl is unsaturated but not aromatic. Heterocyclyl groupscontaining more than one heteroatom may contain different heteroatoms.Heterocyclyl groups may be optionally substituted with one or moresubstituents as defined herein. The heterocyclyl groups herein aremonocyclic ring systems having 6 or 7 member atoms. Monocyclicheterocyclyl includes piperidinyl, piperazinyl, morpholinyl andhexahydro-1,4-oxazepinyl.

“Member atoms” refers to the atom or atoms that form a chain or ring.Where more than one member atom is present in a chain and within a ring,each member atom is covalently bound to an adjacent member atom in thechain or ring. Atoms that make up a substituent group on a chain or ringare not member atoms in the chain or ring.

“Optionally substituted” indicates that a group, such as heteroaryl, maybe unsubstituted or substituted with one or more substituents as definedherein.

“Substituted” in reference to a group indicates that a hydrogen atomattached to a member atom within a group is replaced. It should beunderstood that the term “substituted” includes the implicit provisionthat such substitution be in accordance with the permitted valence ofthe substituted atom and the substituent and that the substitutionresults in a stable compound (i.e. one that does not spontaneouslyundergo transformation such as by rearrangement, cyclization, orelimination). In certain embodiments, a single atom may be substitutedwith more than one substituent as long as such substitution is inaccordance with the permitted valence of the atom. Suitable substituentsare defined herein for each substituted or optionally substituted group.

“Pharmaceutically acceptable” refers to those compounds, salts,materials, compositions, and dosage forms which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation, orother problem or complication, commensurate with a reasonablebenefit/risk ratio.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

DCM Dichloromethane

DMF Dimethylformamide

DMPU 1,3-Dimethyl-3,4,5,6-tetrahydo-2-(1H)-pyrimidinone

DMSO Dimethylsulfoxide

EtOAc Ethyl acetate

g Grams

h hour(s)

HPLC High performance liquid chromatography

LCMS Liquid chromatography mass spectroscopy

L Litre

M Molar

MDAP Mass directed automated preparative HPLC

Me Methyl

MeCN Acetonitrile

MeOH Methanol

mg Milligrams

mins Minutes

ml Millilitres

mmol Millimoles

Rt Retention time

RT Room temperature

SCX Strong Cation Exchange

SPE Solid Phase Extraction

TFA Trifluoroacetic acid

THF Tetrahydrofuran

UPLC Ultra high performance liquid chromatography

UV Ultraviolet

All references to brine are to a saturated aqueous solution of NaCl.

Included within the scope of the “compounds of the invention” are allsolvates (including hydrates), complexes, polymorphs, prodrugs,radiolabelled derivatives, stereoisomers and optical isomers of thecompounds of formula (I) and salts thereof.

The compounds of the invention may exist in solid or liquid form. In thesolid state, the compounds of the invention may exist in crystalline ornoncrystalline form, or as a mixture thereof. For compounds of theinvention that are in crystalline form, the skilled artisan willappreciate that pharmaceutically acceptable solvates may be formedwherein solvent molecules are incorporated into the crystalline latticeduring crystallization. Solvates may involve nonaqueous solvents such asethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, orthey may involve water as the solvent that is incorporated into thecrystalline lattice. Solvates wherein water is the solvent that isincorporated into the crystalline lattice are typically referred to as“hydrates”. Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water. The inventionincludes all such solvates.

The skilled artisan will further appreciate that certain compounds ofthe invention that exist in crystalline form, including the varioussolvates thereof, may exhibit polymorphism (i.e. the capacity to occurin different crystalline structures). These different crystalline formsare typically known as “polymorphs”. The invention includes all suchpolymorphs. Polymorphs have the same chemical composition but differ inpacking, geometrical arrangement, and other descriptive properties ofthe crystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. The skilled artisan willappreciate that different polymorphs may be produced, for example, bychanging or adjusting the reaction conditions or reagents, used inmaking the compound. For example, changes in temperature, pressure, orsolvent may result in polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

In one aspect, the present invention providesN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideor a salt thereof in crystalline form.

In one embodiment, the present invention providesN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidein crystalline form.

In another embodiment, the present invention provides crystallineN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidecharacterised in that it provides an XRPD (X-ray powder diffraction)pattern having peaks (°2θ) at about 4.5, about 11.7 and/or about 12.9.

In another embodiment, the present invention provides crystallineN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidecharacterised in that it provides an XRPD pattern comprising peakssubstantially as set out in Table 2.

In another embodiment, the present invention provides crystallineN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidecharacterised in that it provides an XRPD pattern substantially inaccordance with FIG. 2.

In a further aspect, the present invention provides6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazoleor a salt thereof in crystalline form.

In one embodiment, the present invention provides6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride in crystalline form.

In another embodiment, the present invention provides crystalline6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride characterised in that it provides an XRPD (X-ray powderdiffraction) pattern having peaks (°2θ) at about 5.2, about 10.3 and/orabout 12.8.

In another embodiment, the present invention provides crystalline6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride characterised in that it provides an XRPD patterncomprising peaks substantially as set out in Table 1.

In a further embodiment, the present invention provides crystalline6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride characterised in that it provides an XRPD patternsubstantially in accordance with FIG. 1.

When it is indicated herein that there is a peak in an XRPD pattern at agiven value, it is typically meant that the peak is within ±0.2 of thevalue quoted.

The invention also includes isotopically-labelled compounds, which areidentical to the compounds of formula (I) and salts thereof, but for thefact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass number mostcommonly found in nature. Examples of isotopes that can be incorporatedinto the compounds of the invention include isotopes of hydrogen,carbon, nitrogen, oxygen and fluorine, such as ²H, ³H, ¹¹C, ¹⁴C and ¹⁸F.

The compounds according to formula (I) may contain one or moreasymmetric center (also referred to as a chiral center) and may,therefore, exist as individual enantiomers, diastereomers, or otherstereoisomeric forms, or as mixtures thereof. Chiral centers, such aschiral carbon atoms, may also be present in a substituent such as analkyl group. Where the stereochemistry of a chiral center present informula (I), or in any chemical structure illustrated herein, is notspecified the structure is intended to encompass any stereoisomer andall mixtures thereof. Thus, compounds according to formula (I)containing one or more chiral center may be used as racemic mixtures,enantiomerically enriched mixtures, or as enantiomerically pureindividual stereoisomers.

Individual stereoisomers of a compound according to formula (I) whichcontain one or more asymmetric center may be resolved by methods knownto those skilled in the art. For example, such resolution may be carriedout (1) by formation of diastereoisomeric salts, complexes or otherderivatives; (2) by selective reaction with a stereoisomer-specificreagent, for example by enzymatic oxidation or reduction; or (3) bygas-liquid or liquid chromatography in a chiral enviornment, forexample, on a chiral support such as silica with a bound chiral ligandor in the presence of a chiral solvent. The skilled artisan willappreciate that where the desired stereoisomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step is required to liberate the desired form. Alternatively,specific stereoisomers may be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer to the other by asymmetric transformation.

The compounds according to formula (I) may also contain centers ofgeometric asymmetry. Where the stereochemistry of a center of geometricasymmetry present in formula (I), or in any chemical structureillustrated herein, is not specified, the structure is intended toencompass the trans geometric isomer, the cis geometric isomer, and allmixtures thereof. Likewise, all tautomeric forms are also included informula (I) whether such tautomers exist in equilibrium or predominatelyin one form.

It is to be understood that the references herein to compounds offormula (I) and salts thereof covers the compounds of formula (I) asfree acids or free bases, or as salts thereof, for example aspharmaceutically acceptable salts thereof. Thus, in one embodiment, theinvention is directed to compounds of formula (I) as the free acid orfree base. In another embodiment, the invention is directed to compoundsof formula (I) and salts thereof. In a further embodiment, the inventionis directed to compounds of formula (I) and pharmaceutically acceptablesalts thereof.

The skilled artisan will appreciate that pharmaceutically acceptablesalts of the compounds according to formula (I) may be prepared. Indeed,in certain embodiments of the invention, pharmaceutically acceptablesalts of the compounds according to formula (I) may be preferred overthe respective free base or free acid because such salts may impartgreater stability or solubility to the molecule thereby facilitatingformulation into a dosage form. Accordingly, the invention is furtherdirected to compounds of formula (I) and pharmaceutically acceptablesalts thereof.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the desired biological activity of the subjectcompound and exhibit minimal undesired toxicological effects. Thesepharmaceutically acceptable salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelyreacting the purified compound in its free acid or free base form, or anon-pharmaceutically acceptable salt, with a suitable base or acid,respectively.

Salts and solvates having non-pharmaceutically acceptable counter-ionsor associated solvents are within the scope of the present invention,for example, for use as intermediates in the preparation of othercompounds of formula (I) and their pharmaceutically acceptable salts.Thus one embodiment of the invention embraces compounds of formula (I)and salts thereof.

In certain embodiments, compounds according to formula (I) may containan acidic functional group. Suitable pharmaceutically-acceptable saltsinclude salts of such acidic functional groups. Representative saltsinclude pharmaceutically acceptable metal salts such as sodium,potassium, lithium, calcium, magnesium, aluminum, and zinc salts;carbonates and bicarbonates of a pharmaceutically acceptable metalcation such as sodium, potassium, lithium, calcium, magnesium, aluminum,and zinc; pharmaceutically acceptable organic primary, secondary, andtertiary amines including aliphatic amines, aromatic amines, aliphaticdiamines, and hydroxy alkylamines such as methylamine, ethylamine,2-hydroxyethylamine, diethylamine, TEA, ethylenediamine, ethanolamine,diethanolamine, and cyclohexylamine.

In certain embodiments, compounds according to formula (I) may contain abasic functional group and are therefore capable of formingpharmaceutically acceptable acid addition salts by treatment with asuitable acid. Suitable acids include pharmaceutically acceptableinorganic acids and pharmaceutically acceptable organic acids.Representative pharmaceutically acceptable acid addition salts includehydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate,sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate,propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate,acrylate, fumarate, malate, tartrate, citrate, salicylate,p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate,succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate,hydroxynaphthoate, mandelate, tannate, formate, stearate, ascorbate,palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate,glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate(esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate),p-aminobenzenesulfonate, p-toluenesulfonate (tosylate), andnapthalene-2-sulfonate. In one embodiment, the pharmaceuticallyacceptable addition salt is a hydrochloride. In a further embodiment,the pharmaceutically acceptable addition salt is a mandelate such as the(R)-mandelate.

In one embodiment, the invention provides a compound which is:

-   N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound which is:

-   6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole;

or a pharmaceutically acceptable salt thereof.

Compound Preparation

The compounds of the invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the Examplessection.

Process A

Compounds of formula (I), wherein R¹, R², R³ and R⁴ are as definedabove, or salts thereof, may be prepared from compounds of formula (II)

wherein R² and R³ are as defined above and R^(4a) is methyl or asuitable protecting group such as benzenesulphonyl, by treatment with asuitable boronic acid or boronate ester such as4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (commerciallyavailable), in the presence of a suitable palladium catalyst such aschloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane, in a suitable solvent such as amixture of 1,4-dioxane and water in a suitable ratio, for example about4:1, in the presence of a suitable base such as sodium bicarbonate, andat a suitable temperature such as from about 80° C. to about 150° C.,for example about 120° C.

The R¹ group introduced via the boronic acid or boronate ester may beprotected by a suitable protecting group such as atert-butyldimethylsilyl group and an additional deprotection step may berequired, for example treatment with a suitable fluoride such astetra-n-butylammonium fluoride, in a suitable solvent such astetrahydrofuran, and at a suitable temperature such as room temperature,for example about 20° C.

If necessary, for compounds of formula (II) wherein R^(4a) is a suitableprotecting group, the protecting group such as benzenesulphonyl maysubsequently be removed by treatment with a suitable aqueous inorganicbase such as aqueous sodium hydroxide, in a suitable solvent such asisopropanol, and at a suitable temperature such as room temperature, forexample about 20° C.

Compounds of formula (II), wherein R², R³ and R^(4a) are as definedabove, may be prepared from compounds of formula (III)

wherein R^(4a) is as defined above and X¹ is a suitable leaving groupsuch as Br, by treatment with an amine of formula HNR²R³, wherein R² andR³ are defined as above, in a suitable solvent such as dichloromethane,and at a suitable temperature such as room temperature, for exampleabout 20° C.

Compounds of formula (III), wherein R^(4a) is as defined above and X¹ isBr, may be prepared from compounds of formula (IV)

wherein R^(4a) is as defined above, by treatment with a suitablebrominating agent such as carbon tetrabromide and a suitable phosphinesuch as triphenylphosphine, in a suitable solvent such asdichloromethane, and at a suitable temperature such as from about 0° C.to about 50° C., for example about 0° C. warming to about 20° C. afteraddition.

Or, alternatively, compounds of formula (III), wherein R^(4a) is asdefined above and X¹ is Br, may be prepared from compounds of formula(IV) wherein R^(4a) is as defined above, by treatment with a suitablebrominating agent such as triphenylphosphine dibromide, in a suitablesolvent such as dichloromethane, and at a suitable temperature such asfrom about 0° C. to about 50° C., for example about 0° C.

Compounds of formula (IV), wherein R^(4a) is as defined above, may beprepared from compounds of formula (V)

wherein R^(4a) is as defined above, by treatment with a suitablereducing agent such as diisobutylaluminium hydride, in a suitablesolvent such as tetrahydrofuran, and at a suitable temperature such asfrom about −50° C. to about 0° C., for example about 0° C.

Compounds of formula (V), wherein R^(4a) is as defined above, may beprepared from compounds of formula (VI)

wherein R^(4a) is as defined above, by treatment with a suitable halidesuch as ethyl 2-chloro-1,3-oxazole-5-carboxylate (commerciallyavailable), in the presence of a suitable palladium catalyst such astetrakis(triphenylphosphine)palladium (0), in a suitable solvent such asa N,N-dimethylformamide, in the presence of a suitable iodide such assodium iodide, and under microwave irradiation at a suitable temperaturesuch as from about 80° C. to about 150° C., for example about 100° C.

Or, alternatively, compounds of formula (V), wherein R^(4a) is asdefined above, may be prepared from compounds of formula (VII) asdefined below, by treatment with a suitable stannane such ashexamethylditin, in the presence of a suitable palladium catalyst suchas tetrakis(triphenylphosphine)palladium (0) and a suitable base such astriethylamine, in a suitable solvent such as toluene, and at a suitabletemperature such as from about 100° C. to about 200° C., for exampleabout 120° C., followed by treatment with a suitable halide such asmethyl 2-chloro-1,3-oxazole-5-carboxylate (commercially available), inthe presence of a suitable iodide such as copper (I) iodide, and asuitable palladium catalyst such astetrakis(triphenylphosphine)palladium (0), in a suitable solvent such as1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, and at a suitabletemperature such as from about 50° C. to about 150° C., for exampleabout 85° C.

Compounds of formula (VI), wherein R^(4a) is as defined above, may beprepared from compounds of formula (VII)

wherein R^(4a) is as defined above, by treatment with a suitablestannane such as hexamethylditin, in the presence of a suitablepalladium catalyst such as tetrakis(triphenylphosphine)palladium (0), ina suitable solvent such as xylene, in the presence of a suitable basesuch as triethylamine, and at a suitable temperature such as from about100° C. to about 200° C., for example about 150° C.

Compounds of formula (VII), wherein R^(4a) is methyl, may be preparedfrom compounds such as the compound of formula (VIII)

by methylation using a suitable base such as sodium hydride, in asuitable solvent such as tetrahydrofuran, and at a suitable temperaturesuch as about 0° C., followed by addition of an alkylating agent such asiodomethane and stirring at a suitable temperature such as roomtemperature, for example about 20° C.

The compound of formula (VIII) is commercially available.

Compounds of formula (VII), wherein R^(4a) is a suitable protectinggroup such as benzenesulphonyl, may be prepared from the compound withformula (VIII) as defined above, by treatment with a suitable base suchas sodium hydride in a suitable solvent such as N,N-dimethylformamide,and at a suitable temperature such as from about 0° C. to about 20° C.,for example about 0° C., followed by treatment with a suitablesulphonylating agent such as benzensulphonyl chloride, at a suitabletemperature such as from about 0° C. to about 50° C., for example about0° C. warming to about 20° C. after addition.

Or alternatively, compounds of formula (VII), wherein R^(4a) is asuitable protecting group such as benzenesulphonyl, may be prepared fromthe compound with formula (VIII) as defined above, by treatment with asuitable base, such as sodium hydroxide and a suitable phase transfercatalyst such as tetra-n-butylammonium bisulphate, in a suitable solventsuch as tetrahydrofuran and at a suitable temperature such as from about0° C. to about 20° C., for example about 20° C., followed by treatmentwith a suitable sulphonylating agent such as benzene sulphonyl chloride,at a suitable temperature such as from about 0° C. to about 50° C., forexample about 25° C.

Process B

Compounds of formula (I), wherein R¹, R² and R³ are as defined above andR⁴ is hydrogen, or salts thereof, may be prepared from compounds offormula (IX)

wherein R¹, R², R³ are as defined above and R^(4b) is a suitableprotecting group such as benzenesulphonyl, by treatment with a suitableaqueous inorganic base such as aqueous sodium hydroxide, in a suitablesolvent such as 1,4-dioxane, and at a suitable temperature such as roomtemperature, for example about 20° C.

Compounds of formula (IX), wherein R¹, R², R³ and R^(4b) are as definedabove, may be prepared from compounds of formula (X)

wherein, R¹ and R^(4b) are as defined above and X² is a suitable leavinggroup such as Br, by treatment with an amine of formula HNR²R³, whereinR² and R³ are as defined above, in a suitable solvent such asdichloromethane, and at a suitable temperature such as room temperature,for example about 20° C.

Compounds of formula (X), wherein R¹ and R^(4b) are as defined above andX² is Br, may be prepared from compounds of formula (XI)

wherein R¹ and R^(4b) are as defined above, by treatment with a suitablebrominating agent such as carbon tetrabromide and a suitable phosphinesuch as triphenylphosphine, in a suitable solvent such asdichloromethane, and at a suitable temperature such as from about 0° C.to about 50° C., for example about 0° C. warming to room temperatureafter addition.

Compounds of formula (XI), wherein R¹ and R^(4b) are as defined above,may be prepared from compounds of formula (XII)

wherein R¹ and R^(4b) are as defined above, by treatment with a suitablereducing agent such as diisobutylaluminium hydride, in a suitablesolvent such as dichloromethane, and at a suitable temperature such asfrom about −50° C. to about 0° C., for example about −20° C.

Compounds of formula (XII), wherein R¹ and R^(4b) are as defined above,may be prepared from compounds of formula (XIII)

wherein R^(4b) is as defined above, by treatment with a suitable boronicacid or boronate ester such as{1-[(1,1-dimethylethyl)(dimethyl)silyl]-1H-indol-4-yl}boronic acid(commercially available), in the presence of a suitable palladiumcatalyst such aschloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane, in a suitable solvent such as amixture of 1,4-dioxane and water in a suitable ratio, for example about10:1, in the presence of a suitable base such as potassium phosphatetribasic, and at a suitable temperature such as about 80° C. to about150° C., for example about 100° C. Alternatively, this process may becarried out under microwave irradiation, and at a suitable temperaturesuch as from about 80° C. to about 150° C., for example about 120° C.

Boronate esters of formula (XIV), wherein R⁷ is as defined above, R⁸ isC₁₋₆alkyl, —OR⁶ or halo, wherein R⁶ is as defined above and n=0 or 1,may be prepared from compounds of formula (XV)

wherein R⁸ is as defined above and n=0 or 1, by treatment with asuitable sulphonyl chloride of formula R⁷SO₂Cl such as methanesulphonylchloride, in a suitable solvent such as pyridine, and at a suitabletemperature such as room temperature, for example about 20° C.

Compounds of formula (XV) wherein R⁸ is as defined above and n=0 or 1,may be prepared from compounds of formula (XVI)

wherein R⁸ is as defined above, for which a range of analogues arecommercially available, by treatment with a suitable borolane such as4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane, in thepresence of a suitable palladium catalyst such asdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct, in the presence of a suitable base such aspotassium acetate, in a suitable solvent such as 1,4-dioxane, and at asuitable temperature such as from about 50° C. to about 120° C., forexample about 80° C.

Thus, in one embodiment, the invention provides a process for preparinga compound of the invention comprising:

a) reacting a compound of formula (II)

wherein R² and R³ are as defined above and R^(4a) is methyl or asuitable protecting group, with a suitable boronic acid or boronateester, followed where necessary by deprotection; or

b) for a compound of formula (I) wherein R¹, R² and R³ are as definedabove and R⁴ is hydrogen, reacting a compound of formula (IX)

wherein R¹, R², R³ and R^(4b) are as defined above, with a suitableaqeuous inorganic base.

Methods of Use

The compounds of the invention are inhibitors of kinase activity, inparticular PI3-kinase activity. Compounds which are PI3-kinaseinhibitors may be useful in the treatment of disorders wherein theunderlying pathology is (at least in part) attributable to inappropriatePI3-kinase activity, such as asthma and chronic obstructive pulmonarydisease (COPD). “Inappropriate PI3-kinase activity” refers to anyPI3-kinase activity that deviates from the normal PI3-kinase activityexpected in a particular patient. Inappropriate PI3-kinase may take theform of, for instance, an abnormal increase in activity, or anaberration in the timing and or control of PI3-kinase activity. Suchinappropriate activity may result then, for example, from overexpressionor mutation of the protein kinase leading to inappropriate oruncontrolled activation. Accordingly, in another aspect the invention isdirected to methods of treating such disorders.

Such disorders include respiratory diseases including asthma, chronicobstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis(IPF); viral infections including viral respiratory tract infections andviral exacerbation of respiratory diseases such as asthma and COPD;non-viral respiratory infections including aspergillosis andleishmaniasis; allergic diseases including allergic rhinitis and atopicdermatitis; autoimmune diseases including rheumatoid arthritis andmultiple sclerosis; inflammatory disorders including inflammatory boweldisease; cardiovascular diseases including thrombosis andatherosclerosis; hematologic malignancies; neurodegenerative diseases;pancreatitis; multiorgan failure; kidney diseases; platelet aggregation;cancer; sperm motility; transplantation rejection; graft rejection; lunginjuries; and pain including pain associated with rheumatoid arthritisor osteoarthritis, back pain, general inflammatory pain, post hepaticneuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma),trigeminal neuralgia and Central pain. In one embodiment, such disordersinclude respiratory diseases including asthma and chronic obstructivepulmonary disease (COPD); allergic diseases including allergic rhinitisand atopic dermatitis; autoimmune diseases including rheumatoidarthritis and multiple sclerosis; inflammatory disorders includinginflammatory bowel disease; cardiovascular diseases including thrombosisand atherosclerosis; hematologic malignancies; neurodegenerativediseases; pancreatitis; multiorgan failure; kidney diseases; plateletaggregation; cancer; sperm motility; transplantation rejection; graftrejection; lung injuries; and pain including pain associated withrheumatoid arthritis or osteoarthritis, back pain, general inflammatorypain, post hepatic neuralgia, diabetic neuropathy, inflammatoryneuropathic pain (trauma), trigeminal neuralgia and Central pain

The methods of treatment of the invention comprise administering a safeand effective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof to a patient in need thereof. Individualembodiments of the invention include methods of treating any one of theabove-mentioned disorders by administering a safe and effective amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof to a patient in need thereof.

As used herein, “treat” in reference to a disorder means: (1) toameliorate or prevent the disorder or one or more of the biologicalmanifestations of the disorder, (2) to interfere with (a) one or morepoints in the biological cascade that leads to or is responsible for thedisorder or (b) one or more of the biological manifestations of thedisorder, (3) to alleviate one or more of the symptoms or effectsassociated with the disorder, or (4) to slow the progression of thedisorder or one or more of the biological manifestations of thedisorder.

As indicated above, “treatment” of a disorder includes prevention of thedisorder. The skilled artisan will appreciate that “prevention” is notan absolute term. In medicine, “prevention” is understood to refer tothe prophylactic administration of a drug to substantially diminish thelikelihood or severity of a disorder or biological manifestationthereof, or to delay the onset of such disorder or biologicalmanifestation thereof.

As used herein, “safe and effective amount” in reference to a compoundof formula (I) or a pharmaceutically acceptable salt thereof or otherpharmaceutically-active agent means an amount of the compound sufficientto treat the patient's condition but low enough to avoid serious sideeffects (at a reasonable benefit/risk ratio) within the scope of soundmedical judgment. A safe and effective amount of a compound will varywith the particular compound chosen (e.g. consider the potency,efficacy, and half-life of the compound); the route of administrationchosen; the disorder being treated; the severity of the disorder beingtreated; the age, size, weight, and physical condition of the patientbeing treated; the medical history of the patient to be treated; theduration of the treatment; the nature of concurrent therapy; the desiredtherapeutic effect; and like factors, but can nevertheless be routinelydetermined by the skilled artisan.

As used herein, “patient” refers to a human (including adults andchildren) or other animal. In one embodiment, “patient” refers to ahuman.

The compounds of formula (I) or pharmaceutically acceptable saltsthereof may be administered by any suitable route of administration,including both systemic administration and topical administration.Systemic administration includes oral administration, parenteraladministration, transdermal administration and rectal administration.Parenteral administration refers to routes of administration other thanenteral or transdermal, and is typically by injection or infusion.Parenteral administration includes intravenous, intramuscular, andsubcutaneous injection or infusion. Topical administration includesapplication to the skin as well as intraocular, otic, intravaginal,inhaled and intranasal administration. Inhalation refers toadministration into the patient's lungs whether inhaled through themouth or through the nasal passages. In one embodiment, the compounds offormula (I) or pharmaceutically acceptable salts thereof may beadministered orally. In another embodiment, the compounds of formula (I)or pharmaceutically acceptable salts thereof may be administered byinhalation. In a further embodiment, the compounds of formula (I) orpharmaceutically acceptable salts thereof may be administeredintranasally.

The compounds of formula (I) or pharmaceutically acceptable saltsthereof may be administered once or according to a dosing regimenwherein a number of doses are administered at varying intervals of timefor a given period of time. For example, doses may be administered one,two, three, or four times per day. In one embodiment, a dose isadministered once per day. In a further embodiment, a dose isadministered twice per day. Doses may be administered until the desiredtherapeutic effect is achieved or indefinitely to maintain the desiredtherapeutic effect. Suitable dosing regimens for a compound of formula(I) or a pharmaceutically acceptable salt thereof depend on thepharmacokinetic properties of that compound, such as absorption,distribution, and half-life, which can be determined by the skilledartisan. In addition, suitable dosing regimens, including the durationsuch regimens are administered, for a compound of formula (I) or apharmaceutically acceptable salt thereof depend on the disorder beingtreated, the severity of the disorder being treated, the age andphysical condition of the patient being treated, the medical history ofthe patient to be treated, the nature of concurrent therapy, the desiredtherapeutic effect, and like factors within the knowledge and expertiseof the skilled artisan. It will be further understood by such skilledartisans that suitable dosing regimens may require adjustment given anindividual patient's response to the dosing regimen or over time asindividual patient needs change.

Typical daily dosages may vary depending upon the particular route ofadministration chosen. Typical daily dosages for oral administrationrange from 0.001 mg to 50 mg per kg of total body weight, for examplefrom 1 mg to 10 mg per kg of total body weight. For example, dailydosages for oral administration may be from 0.5 mg to 2 g per patient,such as 10 mg to 1 g per patient.

Additionally, the compounds of formula (I) may be administered asprodrugs. As used herein, a “prodrug” of a compound of formula (I) is afunctional derivative of the compound which, upon administration to apatient, eventually liberates the compound of formula (I) in vivo.Administration of a compound of formula (I) as a prodrug may enable theskilled artisan to do one or more of the following: (a) modify the onsetof the activity of the compound in vivo; (b) modify the duration ofaction of the compound in vivo; (c) modify the transportation ordistribution of the compound in vivo; (d) modify the solubility of thecompound in vivo; and (e) overcome a side effect or other difficultyencountered with the compound. Typical functional derivatives used toprepare prodrugs include modifications of the compound that arechemically or enzymatically cleavable in vivo. Such modifications, whichinclude the preparation of phosphates, amides, esters, thioesters,carbonates, and carbamates, are well known to those skilled in the art.

In one aspect, the invention thus provides a method of treating adisorder mediated by inappropriate PI3-kinase activity comprisingadministering a safe and effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof to a patient in needthereof. In one embodiment, the invention provides a method of treatinga disorder mediated by inappropriate PI3-kinase activity comprisingadministering a safe and effective amount ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideor a pharmaceutically acceptable salt thereof to a patient in needthereof. In another embodiment, the invention provides a method oftreating a disorder mediated by inappropriate PI3-kinase activitycomprising administering a safe and effective amount ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(R)-mandelate to a patient in need thereof. In another embodiment, theinvention provides a method of treating a disorder mediated byinappropriate PI3-kinase activity comprising administering a safe andeffective amount of6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazoleor a pharmaceutically acceptable salt thereof to a patient in needthereof. In a further embodiment, the invention provides a method oftreating a disorder mediated by inappropriate PI3-kinase activitycomprising administering a safe and effective amount of6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride to a patient in need thereof.

In one embodiment, the disorder mediated by inappropriate PI3-kinaseactivity is selected from the group consisting of respiratory diseases(including asthma, chronic obstructive pulmonary disease (COPD) andidiopathic pulmonary fibrosis (IPF)); viral infections (including viralrespiratory tract infections and viral exacerbation of respiratorydiseases such as asthma and COPD); non-viral respiratory infections(including aspergillosis and leishmaniasis); allergic diseases(including allergic rhinitis and atopic dermatitis); autoimmune diseases(including rheumatoid arthritis and multiple sclerosis); inflammatorydisorders (including inflammatory bowel disease); cardiovasculardiseases (including thrombosis and atherosclerosis); hematologicmalignancies; neurodegenerative diseases; pancreatitis; multiorganfailure; kidney diseases; platelet aggregation; cancer; sperm motility;transplantation rejection; graft rejection; lung injuries; and pain(including pain associated with rheumatoid arthritis or osteoarthritis,back pain, general inflammatory pain, post hepatic neuralgia, diabeticneuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgiaand Central pain).

In one embodiment, the disorder mediated by inappropriate PI3-kinaseactivity is a respiratory disease. In another embodiment, the disordermediated by inappropriate PI3-kinase activity is asthma. In anotherembodiment, the disorder mediated by inappropriate PI3-kinase activityis chronic obstructive pulmonary disease (COPD). In a furtherembodiment, the disorder mediated by inappropriate PI3-kinase activityis idiopathic pulmonary fibrosis (IPF).

In one embodiment, the disorder mediated by inappropriate PI3-kinaseactivity is pain.

In one embodiment, the present invention provides a method of treating arespiratory disease comprising administering a safe and effective amountofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideor a pharmaceutically acceptable salt thereof to a patient in needthereof.

In another embodiment, the present invention provides a method oftreating asthma comprising administering a safe and effective amount ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideor a pharmaceutically acceptable salt thereof to a patient in needthereof.

In another embodiment, the present invention provides a method oftreating a respiratory disease comprising administering a safe andeffective amount ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(R)-mandelate to a patient in need thereof.

In another embodiment, the present invention provides a method oftreating asthma comprising administering a safe and effective amount ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(R)-mandelate to a patient in need thereof.

In another embodiment, the present invention provides a method oftreating a respiratory disease comprising administering a safe andeffective amount of6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazoleor a pharmaceutically acceptable salt thereof to a patient in needthereof.

In another embodiment, the present invention provides a method oftreating asthma comprising administering a safe and effective amount of6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazoleor a pharmaceutically acceptable salt thereof to a patient in needthereof.

In another embodiment, the present invention provides a method oftreating a respiratory disease comprising administering a safe andeffective amount of6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride to a patient in need thereof.

In a further embodiment, the present invention provides a method oftreating asthma comprising administering a safe and effective amount of6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride to a patient in need thereof.

In one aspect, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in medical therapy. Inone embodiment, the invention providesN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideor a pharmaceutically acceptable salt thereof for use in medicaltherapy. In another embodiment, the invention providesN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(R)-mandelate for use in medical therapy. In another embodiment, theinvention provides6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazoleor a pharmaceutically acceptable salt thereof for use in medicaltherapy. In a further embodiment, the invention provides6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride for use in medical therapy.

In another aspect, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment of adisorder mediated by inappropriate PI3-kinase activity. In oneembodiment, the invention providesN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideor a pharmaceutically acceptable salt thereof for use in the treatmentof a disorder mediated by inappropriate PI3-kinase activity. In anotherembodiment, the invention providesN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(R)-mandelate or use in the treatment of a disorder mediated byinappropriate PI3-kinase activity. In another embodiment, the inventionprovides6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazoleor a pharmaceutically acceptable salt thereof for use in the treatmentof a disorder mediated by inappropriate PI3-kinase activity. In afurther embodiment, the invention provides6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride for use in the treatment of a disorder mediated byinappropriate PI3-kinase activity.

In a further aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment of a disordermediated by inappropriate PI3-kinase activity. In one embodiment, theinvention provides the use ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideor a pharmaceutically acceptable salt thereof in the manufacture of amedicament for use in the treatment of a disorder mediated byinappropriate PI3-kinase activity. In another embodiment, the inventionprovides the use ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(R)-mandelate in the manufacture of a medicament for use in thetreatment of a disorder mediated by inappropriate PI3-kinase activity.In another embodiment, the invention provides the use of6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazoleor a pharmaceutically acceptable salt thereof in the manufacture of amedicament for use in the treatment of a disorder mediated byinappropriate PI3-kinase activity. In a further embodiment, theinvention provides the use of6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride in the manufacture of a medicament for use in thetreatment of a disorder mediated by inappropriate PI3-kinase activity.

Compositions

The compounds of formula (I) and pharmaceutically acceptable saltsthereof will normally, but not necessarily, be formulated intopharmaceutical compositions prior to administration to a patient.

Accordingly, in one aspect the invention is directed to pharmaceuticalcompositions comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptableexcipients.

In one embodiment, the present invention provides a pharmaceuticalcomposition comprisingN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideor a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprisingN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(R) mandelate, and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazoleor a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.

In a further embodiment, the present invention provides a pharmaceuticalcomposition comprising6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride, and one or more pharmaceutically acceptable excipients.

In another aspect the invention is directed to pharmaceuticalcompositions comprising 0.05 to 1000 mg of a compound of formula (I) ora pharmaceutically acceptable salt thereof and 0.1 to 2 g of one or morepharmaceutically acceptable excipients.

In a further aspect the invention is directed to a pharmaceuticalcomposition for the treatment or prophylaxis of a disorder mediated byinappropriate PI3-kinase activity comprising a compound of formula (I)or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention is provides a pharmaceuticalcomposition for the treatment or prophylaxis of a disorder mediated byinappropriate PI3-kinase activity comprisingN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideor a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention is provides a pharmaceuticalcomposition for the treatment or prophylaxis of a disorder mediated byinappropriate PI3-kinase activity comprisingN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(R) mandelate.

In one embodiment, the present invention is provides a pharmaceuticalcomposition for the treatment or prophylaxis of a disorder mediated byinappropriate PI3-kinase activity comprising6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazoleor a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention is provides apharmaceutical composition for the treatment or prophylaxis of adisorder mediated by inappropriate PI3-kinase activity comprising6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein a safe and effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof can beextracted and then given to the patient such as with powders or syrups.Alternatively, the pharmaceutical compositions of the invention may beprepared and packaged in unit dosage form wherein each physicallydiscrete unit contains a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. When prepared in unit dosage form, thepharmaceutical compositions of the invention typically may contain, forexample, from 0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100mg of a compound of formula (I) or a pharmaceutically acceptable saltthereof.

The pharmaceutical compositions of the invention typically contain onecompound of formula (I) or a pharmaceutically acceptable salt thereof.

As used herein, “pharmaceutically acceptable excipient” means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient must be compatible with the other ingredients of thepharmaceutical composition when commingled such that interactions whichwould substantially reduce the efficacy of the compound of formula (I)or a pharmaceutically acceptable salt thereof when administered to apatient and interactions which would result in pharmaceuticalcompositions that are not pharmaceutically acceptable are avoided. Inaddition, each excipient must of course be pharmaceutically-acceptableeg of sufficiently high purity.

The compound of formula (I) or a pharmaceutically acceptable saltthereof and the pharmaceutically acceptable excipient or excipients willtypically be formulated into a dosage form adapted for administration tothe patient by the desired route of administration. For example, dosageforms include those adapted for (1) oral administration such as tablets,capsules, caplets, pills, troches, powders, syrups, elixers,suspensions, solutions, emulsions, sachets, and cachets; (2) parenteraladministration such as sterile solutions, suspensions, and powders forreconstitution; (3) transdermal administration such as transdermalpatches; (4) rectal administration such as suppositories; (5) inhalationsuch as aerosols, solutions, and dry powders; and (6) topicaladministration such as creams, ointments, lotions, solutions, pastes,sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting of the compound or compoundsof formula (I) or pharmaceutically acceptable salts thereof onceadministered to the patient from one organ, or portion of the body, toanother organ, or portion of the body. Certain pharmaceuticallyacceptable excipients may be chosen for their ability to enhance patientcompliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweetners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, hemectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what other excipientsare present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically-acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

Accordingly, in another aspect the invention is directed to process forthe preparation of a pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof and one ormore pharmaceutically acceptable excipients which comprises mixing theingredients. A pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof may beprepared by, for example, admixture at ambient temperature andatmospheric pressure.

In one embodiment, the compounds of formula (I) or pharmaceuticallyacceptable salts thereof will be formulated for oral administration. Inanother embodiment, the compounds of formula (I) or pharmaceuticallyacceptable salts thereof will be formulated for inhaled administration.In a further embodiment, the compounds of formula (I) orpharmaceutically acceptable salts thereof will be formulated forintranasal administration.

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising a safe and effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereofand a diluent or filler. Suitable diluents and fillers include lactose,sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potatostarch, and pre-gelatinized starch), cellulose and its derivatives (e.g.microcrystalline cellulose), calcium sulfate, and dibasic calciumphosphate. The oral solid dosage form may further comprise a binder.Suitable binders include starch (e.g. corn starch, potato starch, andpre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid,tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g.microcrystalline cellulose). The oral solid dosage form may furthercomprise a disintegrant. Suitable disintegrants include crospovidone,sodium starch glycolate, croscarmelose, alginic acid, and sodiumcarboxymethyl cellulose. The oral solid dosage form may further comprisea lubricant. Suitable lubricants include stearic acid, magnesuimstearate, calcium stearate, and talc.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I) or pharmaceutically acceptable saltsthereof may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds offormula (I) or pharmaceutically acceptable salts thereof may be coupledto a class of biodegradable polymers useful in achieving controlledrelease of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

In another aspect, the invention is directed to a liquid oral dosageform. Oral liquids such as solution, syrups and elixirs can be preparedin dosage unit form so that a given quantity contains a predeterminedamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof. Syrups can be prepared by dissolving the compound offormula (I) or a pharmaceutically acceptable salt thereof in a suitablyflavored aqueous solution, while elixirs are prepared through the use ofa non-toxic alcoholic vehicle. Suspensions can be formulated bydispersing the compound of formula (I) or a pharmaceutically acceptablesalt thereof in a non-toxic vehicle. Solubilizers and emulsifiers suchas ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers,preservatives, flavor additive such as peppermint oil or naturalsweeteners or saccharin or other artificial sweeteners, and the like canalso be added.

In another aspect, the invention is directed to a dosage form adaptedfor administration to a patient by inhalation, for example as a drypowder, an aerosol, a suspension, or a solution composition. In oneembodiment, the invention is directed to a dosage form adapted foradministration to a patient by inhalation as a dry powder. In a furtherembodiment, the invention is directed to a dosage form adapted foradministration to a patient by inhalation via a nebulizer.

Dry powder compositions for delivery to the lung by inhalation typicallycomprise a compound of formula (I) or a pharmaceutically acceptable saltthereof as a finely divided powder together with one or morepharmaceutically-acceptable excipients as finely divided powders.Pharmaceutically-acceptable excipients particularly suited for use indry powders are known to those skilled in the art and include lactose,starch, mannitol, and mono-, di-, and polysaccharides. The finelydivided powder may be prepared by, for example, micronisation andmilling. Generally, the size-reduced (eg micronised) compound can bedefined by a D₅₀ value of about 1 to about 10 microns (for example asmeasured using laser diffraction).

The dry powder may be administered to the patient via a reservoir drypowder inhaler (RDPI) having a reservoir suitable for storing multiple(un-metered doses) of medicament in dry powder form. RDPIs typicallyinclude a means for metering each medicament dose from the reservoir toa delivery position. For example, the metering means may comprise ametering cup, which is movable from a first position where the cup maybe filled with medicament from the reservoir to a second position wherethe metered medicament dose is made available to the patient forinhalation.

Alternatively, the dry powder may be presented in capsules (e.g. gelatinor plastic), cartridges, or blister packs for use in a multi-dose drypowder inhaler (MDPI). MDPIs are inhalers wherein the medicament iscomprised within a multi-dose pack containing (or otherwise carrying)multiple defined doses (or parts thereof) of medicament. When the drypowder is presented as a blister pack, it comprises multiple blistersfor containment of the medicament in dry powder form. The blisters aretypically arranged in regular fashion for ease of release of themedicament therefrom. For example, the blisters may be arranged in agenerally circular fashion on a disc-form blister pack, or the blistersmay be elongate in form, for example comprising a strip or a tape. Eachcapsule, cartridge, or blister may, for example, contain between 20μg-10 mg of the compound of formula (I) or a pharmaceutically acceptablesalt thereof.

Aerosols may be formed by suspending or dissolving a compound of formula(I) or a pharmaceutically acceptable salt thereof in a liquifiedpropellant. Suitable propellants include halocarbons, hydrocarbons, andother liquified gases. Representative propellants include:trichlorofluoromethane (propellant 11), dichlorofluoromethane(propellant 12), dichlorotetrafluoroethane (propellant 114),tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a),difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane(HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane,isobutane, and pentane. Aerosols comprising a compound of formula (I) ora pharmaceutically acceptable salt thereof will typically beadministered to a patient via a metered dose inhaler (MDI). Such devicesare known to those skilled in the art.

The aerosol may contain additional pharmaceutically-acceptableexcipients typically used with MDIs such as surfactants, lubricants,cosolvents and other excipients to improve the physical stability of theformulation, to improve valve performance, to improve solubility, or toimprove taste.

There is thus provided as a further aspect of the invention apharmaceutical aerosol formulation comprising a compound of formula (I)or a pharmaceutically acceptable salt thereof and a fluorocarbon orhydrogen-containing chlorofluorocarbon as propellant, optionally incombination with a surfactant and/or a cosolvent.

According to another aspect of the invention, there is provided apharmaceutical aerosol formulation wherein the propellant is selectedfrom 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane andmixtures thereof.

The formulations of the invention may be buffered by the addition ofsuitable buffering agents.

Capsules and cartridges for use in an inhaler or insufflator, of forexample gelatine, may be formulated containing a powder mix forinhalation of a compound of formula (I) or a pharmaceutically acceptablesalt thereof and a suitable powder base such as lactose or starch. Eachcapsule or cartridge may generally contain from 20 μg to 10 mg of thecompound of formula (I) or pharmaceutically acceptable salt thereof.Alternatively, the compound of formula (I) or pharmaceuticallyacceptable salt thereof may be presented without excipients such aslactose.

The proportion of the active compound of formula (I) or pharmaceuticallyacceptable salt thereof in the local compositions according to theinvention depends on the precise type of formulation to be prepared butwill generally be within the range of from 0.001 to 10% by weight.Generally, for most types of preparations, the proportion used will bewithin the range of from 0.005 to 1%, for example from 0.01 to 0.5%.However, in powders for inhalation or insufflation the proportion usedwill normally be within the range of from 0.1 to 5%.

Aerosol formulations are preferably arranged so that each metered doseor “puff” of aerosol contains from 20 μg to 10 mg, preferably from 20 μgto 2000 μg, more preferably from about 20 μg to 500 μg of a compound offormula (I). Administration may be once daily or several times daily,for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses eachtime. The overall daily dose with an aerosol will be within the rangefrom 100 μg to 10 mg, preferably from 200 μg to 2000 μg. The overalldaily dose and the metered dose delivered by capsules and cartridges inan inhaler or insufflator will generally be double that delivered withaerosol formulations.

In the case of suspension aerosol formulations, the particle size of theparticulate (e.g., micronised) drug should be such as to permitinhalation of substantially all the drug into the lungs uponadministration of the aerosol formulation and will thus be less than 100microns, desirably less than 20 microns, and in particular in the rangeof from 1 to 10 microns, such as from 1 to 5 microns, more preferablyfrom 2 to 3 microns.

The formulations of the invention may be prepared by dispersal ordissolution of the medicament and a compound of formula (I) or apharmaceutically acceptable salt thereof in the selected propellant inan appropriate container, for example, with the aid of sonication or ahigh-shear mixer. The process is desirably carried out under controlledhumidity conditions.

The chemical and physical stability and the pharmaceutical acceptabilityof the aerosol formulations according to the invention may be determinedby techniques well known to those skilled in the art. Thus, for example,the chemical stability of the components may be determined by HPLCassay, for example, after prolonged storage of the product. Physicalstability data may be gained from other conventional analyticaltechniques such as, for example, by leak testing, by valve deliveryassay (average shot weights per actuation), by dose reproducibilityassay (active ingredient per actuation) and spray distribution analysis.

The stability of the suspension aerosol formulations according to theinvention may be measured by conventional techniques, for example, bymeasuring flocculation size distribution using a back light scatteringinstrument or by measuring particle size distribution by cascadeimpaction or by the “twin impinger” analytical process. As used hereinreference to the “twin impinger” assay means “Determination of thedeposition of the emitted dose in pressurised inhalations usingapparatus A” as defined in British Pharmacopaeia 1988, pages A204-207,Appendix XVII C. Such techniques enable the “respirable fraction” of theaerosol formulations to be calculated. One method used to calculate the“respirable fraction” is by reference to “fine particle fraction” whichis the amount of active ingredient collected in the lower impingementchamber per actuation expressed as a percentage of the total amount ofactive ingredient delivered per actuation using the twin impinger methoddescribed above.

The term “metered dose inhaler” or MDI means a unit comprising a can, asecured cap covering the can and a formulation metering valve situatedin the cap. MDI system includes a suitable channelling device. Suitablechannelling devices comprise for example, a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient such as a mouthpiece actuator.

MDI canisters generally comprise a container capable of withstanding thevapour pressure of the propellant used such as a plastic orplastic-coated glass bottle or preferably a metal can, for example,aluminium or an alloy thereof which may optionally be anodised,lacquer-coated and/or plastic-coated (for example incorporated herein byreference WO96/32099 wherein part or all of the internal surfaces arecoated with one or more fluorocarbon polymers optionally in combinationwith one or more non-fluorocarbon polymers), which container is closedwith a metering valve. The cap may be secured onto the can viaultrasonic welding, screw fitting or crimping. MDIs taught herein may beprepared by methods of the art (e.g. see Byron, above and WO96/32099).Preferably the canister is fitted with a cap assembly, wherein adrug-metering valve is situated in the cap, and said cap is crimped inplace.

In one embodiment of the invention the metallic internal surface of thecan is coated with a fluoropolymer, more preferably blended with anon-fluoropolymer. In another embodiment of the invention the metallicinternal surface of the can is coated with a polymer blend ofpolytetrafluoroethylene (PTFE) and polyethersulfone (PES). In a furtherembodiment of the invention the whole of the metallic internal surfaceof the can is coated with a polymer blend of polytetrafluoroethylene(PTFE) and polyethersulfone (PES).

The metering valves are designed to deliver a metered amount of theformulation per actuation and incorporate a gasket to prevent leakage ofpropellant through the valve. The gasket may comprise any suitableelastomeric material such as, for example, low density polyethylene,chlorobutyl, bromobutyl, EPDM, black and white butadiene-acrylonitrilerubbers, butyl rubber and neoprene. Suitable valves are commerciallyavailable from manufacturers well known in the aerosol industry, forexample, from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK(e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser™).

In various embodiments, the MDIs may also be used in conjunction withother structures such as, without limitation, overwrap packages forstoring and containing the MDIs, including those described in U.S. Pat.Nos. 6,119,853; 6,179,118; 6,315,112; 6,352,152; 6,390,291; and6,679,374, as well as dose counter units such as, but not limited to,those described in U.S. Pat. Nos. 6,360,739 and 6,431,168.

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large-scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method for preparing suspension aerosol formulations ametering valve is crimped onto an aluminium can to form an emptycanister. The particulate medicament is added to a charge vessel andliquefied propellant together with the optional excipients is pressurefilled through the charge vessel into a manufacturing vessel. The drugsuspension is mixed before recirculation to a filling machine and analiquot of the drug suspension is then filled through the metering valveinto the canister. In one example bulk manufacturing method forpreparing solution aerosol formulations a metering valve is crimped ontoan aluminium can to form an empty canister. The liquefied propellanttogether with the optional excipients and the dissolved medicament ispressure filled through the charge vessel into a manufacturing vessel.

In an alternative process, an aliquot of the liquefied formulation isadded to an open canister under conditions which are sufficiently coldto ensure the formulation does not vaporise, and then a metering valvecrimped onto the canister.

Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

Suspensions and solutions comprising a compound of formula (I) or apharmaceutically acceptable salt thereof may also be administered to apatient via a nebulizer. The solvent or suspension agent utilized fornebulization may be any pharmaceutically-acceptable liquid such aswater, aqueous saline, alcohols or glycols, e.g., ethanol,isopropylalcohol, glycerol, propylene glycol, polyethylene glycol, etc.or mixtures thereof. Saline solutions utilize salts which display littleor no pharmacological activity after administration. Both organic salts,such as alkali metal or ammonium halogen salts, e.g., sodium chloride,potassium chloride or organic salts, such as potassium, sodium andammonium salts or organic acids, e.g., ascorbic acid, citric acid,acetic acid, tartaric acid, etc. may be used for this purpose.

Other pharmaceutically-acceptable excipients may be added to thesuspension or solution. The compound of formula (I) or pharmaceuticallyacceptable salt thereof may be stabilized by the addition of aninorganic acid, e.g., hydrochloric acid, nitric acid, sulphuric acidand/or phosphoric acid; an organic acid, e.g., ascorbic acid, citricacid, acetic acid, and tartaric acid, etc., a complexing agent such asEDTA or citric acid and salts thereof; or an antioxidant such asantioxidant such as vitamin E or ascorbic acid. These may be used aloneor together to stabilize the compound of formula (I) or pharmaceuticallyacceptable salt thereof. Preservatives may be added such as benzalkoniumchloride or benzoic acid and salts thereof. Surfactant may be addedparticularly to improve the physical stability of suspensions. Theseinclude lecithin, disodium dioctylsulphosuccinate, oleic acid andsorbitan esters.

In a further aspect, the invention is directed to a dosage form adaptedfor intranasal administration.

Formulations for administration to the nose may include pressurisedaerosol formulations and aqueous formulations administered to the noseby pressurised pump. Formulations which are non-pressurised and adaptedto be administered topically to the nasal cavity are of particularinterest. Suitable formulations contain water as the diluent or carrierfor this purpose. Aqueous formulations for administration to the lung ornose may be provided with conventional excipients such as bufferingagents, tonicity modifying agents and the like. Aqueous formulations mayalso be administered to the nose by nebulisation.

The compounds of formula (I) or pharmaceutically acceptable saltsthereof may be formulated as a fluid formulation for delivery from afluid dispenser, for example a fluid dispenser having a dispensingnozzle or dispensing orifice through which a metered dose of the fluidformulation is dispensed upon the application of a user-applied force toa pump mechanism of the fluid dispenser. Such fluid dispensers aregenerally provided with a reservoir of multiple metered doses of thefluid formulation, the doses being dispensable upon sequential pumpactuations. The dispensing nozzle or orifice may be configured forinsertion into the nostrils of the user for spray dispensing of thefluid formulation into the nasal cavity. A fluid dispenser of theaforementioned type is described and illustrated in WO05/044354, theentire content of which is hereby incorporated herein by reference. Thedispenser has a housing which houses a fluid discharge device having acompression pump mounted on a container for containing a fluidformulation. The housing has at least one finger-operable side leverwhich is movable inwardly with respect to the housing to cam thecontainer upwardly in the housing to cause the pump to compress and pumpa metered dose of the formulation out of a pump stem through a nasalnozzle of the housing. In one embodiment, the fluid dispenser is of thegeneral type illustrated in FIGS. 30-40 of WO05/044354.

Pharmaceutical compositions adapted for intranasal administrationwherein the carrier is a solid include a coarse powder having a particlesize for example in the range 20 to 500 microns which is administered byrapid inhalation through the nasal passage from a container of thepowder held close up to the nose. Suitable compositions wherein thecarrier is a liquid, for administration as a nasal spray or as nasaldrops, include aqueous or oil solutions of the compound of formula (I)or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the patient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

Ointments, creams and gels, may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agent and/or solvents. Such bases may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a solvent such as polyethylene glycol.Thickening agents and gelling agents which may be used according to thenature of the base include soft paraffin, aluminium stearate,cetostearyl alcohol, polyethylene glycols, woolfat, beeswax,carboxypolymethylene and cellulose derivatives, and/or glycerylmonostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or non-aqueous base also comprising one ormore dispersing agents, solubilising agents, suspending agents orpreservatives.

Topical preparations may be administered by one or more applications perday to the affected area; over skin areas occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedby an adhesive reservoir system.

For treatments of the eye or other external tissues, for example mouthand skin, the compositions may be applied as a topical ointment orcream. When formulated in an ointment, the compound of formula (I) or apharmaceutically acceptable salt thereof may be employed with either aparaffinic or a water-miscible ointment base. Alternatively, thecompound of formula (I) or pharmaceutically acceptable salt thereof maybe formulated in a cream with an oil-in-water cream base or awater-in-oil base.

Pharmaceutical compositions adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

The compound and pharmaceutical formulations according to the inventionmay be used in combination with or include one or more other therapeuticagents, for example selected from anti-inflammatory agents,anticholinergic agents (particularly an M₁/M₂/M₃ receptor antagonist),β₂-adrenoreceptor agonists, antiinfective agents, such as antibiotics orantivirals, or antihistamines. The invention thus provides, in a furtheraspect, a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof together with one or more othertherapeutically active agents, for example selected from ananti-inflammatory agent, such as a corticosteroid or an NSAID, ananticholinergic agent, a β₂-adrenoreceptor agonist, an antiinfectiveagent, such as an antibiotic or an antiviral, or an antihistamine. Oneembodiment of the invention encompasses combinations comprising acompound of formula (I) or a pharmaceutically acceptable salt thereoftogether with a β₂-adrenoreceptor agonist, and/or an anticholinergic,and/or a PDE-4 inhibitor, and/or an antihistamine.

In one embodiment, the invention encompasses a method of treating adisorder mediated by inappropriate PI3-kinase activity comprisingadministering a safe and effective amount of a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereoftogether with one or more therapeutically active agents.

Certain compounds of the invention may show selectivity for PI3Kδ overother PI3-kinases. The invention thus provides, in a further aspect, acombination comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof which is selective for PI3Kδ together with acompound or pharmaceutically acceptable salt thereof which is selectivefor another PI3-kinase, for example PI3Kγ.

One embodiment of the invention encompasses combinations comprising oneor two other therapeutic agents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,for example as alkali metal or amine salts or as acid addition salts, orprodrugs, or as esters, for example lower alkyl esters, or as solvates,for example hydrates to optimise the activity and/or stability and/orphysical characteristics, such as solubility, of the therapeuticingredient. It will be clear also that, where appropriate, thetherapeutic ingredients may be used in optically pure form.

In one embodiment, the invention encompasses a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereoftogether with a β₂-adrenoreceptor agonist.

Examples of β₂-adrenoreceptor agonists include salmeterol (which may bea racemate or a single enantiomer such as the R-enantiomer), salbutamol(which may be a racemate or a single enantiomer such as theR-enantiomer), formoterol (which may be a racemate or a singleduastereomer such as the R,R-diastereomer), salmefamol, fenoterolcarmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol,reproterol, bambuterol, indacaterol, terbutaline and salts thereof, forexample the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt ofsalmeterol, the sulphate salt or free base of salbutamol or the fumaratesalt of formoterol. In one embodiment, long-acting β₂-adrenoreceptoragonists, for example, compounds which provide effective bronchodilationfor about 12 hrs or longer, are preferred.

Other β₂-adrenoreceptor agonists include those described in WO02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773,WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 andWO03/042160.

Examples of β₂-adrenoreceptor agonists include:

-   3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)    phenyl]ethyl}amino) hexyl] oxy} butyl) benzenesulfonamide;-   3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl) phenyl]    ethyl}-amino) heptyl] oxy}propyl) benzenesulfonamide;-   4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl)    amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol;-   4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   N-[2-hydroxyl-5-[(1R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide;-   N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;    and-   5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one.

The β₂-adrenoreceptor agonist may be in the form of a salt formed with apharmaceutically acceptable acid selected from sulphuric, hydrochloric,fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic),cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic,naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic,4-chlorobenzoic and 4-phenylbenzoic acid.

Suitable anti-inflammatory agents include corticosteroids. Suitablecorticosteroids which may be used in combination with the compounds offormula (I) or pharmaceutically acceptable salts thereof are those oraland inhaled corticosteroids and their pro-drugs which haveanti-inflammatory activity. Examples include methyl prednisolone,prednisolone, dexamethasone, fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (fluticasone furoate),6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester and6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, beclomethasone esters (for example the17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (for example mometasone furoate),triamcinolone acetonide, rofleponide, ciclesonide (16α,17-[[(R)-cyclohexylmethylene]bis(oxy)]-11β,21-dihydroxy-pregna-1,4-diene-3,20-dione),butixocort propionate, RPR-106541, and ST-126. Preferred corticosteroidsinclude fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester and6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester. In one embodiment the corticosteroid is6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

Examples of corticosteroids may include those described inWO2002/088167, WO2002/100879, WO2002/12265, WO2002/12266, WO2005/005451,WO2005/005452, WO2006/072599 and WO2006/072600.

Non-steroidal compounds having glucocorticoid agonism that may possessselectivity for transrepression over transactivation and that may beuseful in combination therapy include those covered in the followingpatents: WO03/082827, WO98/54159, WO 04/005229, WO04/009017,WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899,WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294,WO04/026248, WO03/061651 and WO03/08277. Further non-steroidal compoundsare covered in: WO2006/000401, WO2006/000398 and WO2006/015870.

Examples of anti-inflammatory agents include non-steroidalanti-inflammatory drugs (NSAID's).

Examples of NSAID's include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists,inhibitors of leukotriene synthesis (for example montelukast), iNOSinhibitors, tryptase and elastase inhibitors, beta-2 integrinantagonists and adenosine receptor agonists or antagonists (e.g.adenosine 2a agonists), cytokine antagonists (for example chemokineantagonists, such as a CCR3 antagonist) or inhibitors of cytokinesynthesis, or 5-lipoxygenase inhibitors. An iNOS (inducible nitric oxidesynthase inhibitor) is preferably for oral administration. Examples ofiNOS inhibitors include those disclosed in WO93/13055, WO98/30537,WO02/50021, WO95/34534 and WO99/62875. Examples of CCR3 inhibitorsinclude those disclosed in WO02/26722.

In one embodiment, the invention provides the use of the compounds offormula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor,especially in the case of a formulation adapted for inhalation. ThePDE4-specific inhibitor useful in this aspect of the invention may beany compound that is known to inhibit the PDE4 enzyme or which isdiscovered to act as a PDE4 inhibitor, and which are only PDE4inhibitors, not compounds which inhibit other members of the PDE family,such as PDE3 and PDE5, as well as PDE4.

Compounds includecis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].Also,cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomilast) and its salts, esters, pro-drugs orphysical forms, which is described in U.S. Pat. No. 5,552,438 issued 3Sep. 1996; this patent and the compounds it discloses are incorporatedherein in full by reference.

Other compounds include AWD-12-281 from Elbion (Hofgen, N. et al. 15thEFMC Int Symp Med Chem (September 6-10, Edinburgh) 1998, Abst P.98; CASreference No. 247584020-9); a 9-benzyladenine derivative nominatedNCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; abenzodiazepine PDE4 inhibitor identified as Cl-1018 (PD-168787) andattributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakkoin WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (September 19-23, Geneva)1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No162401-32-3) and a pthalazinone (WO99/47505, the disclosure of which ishereby incorporated by reference) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162), andT2585.

Further compounds are disclosed in the published international patentapplication WO04/024728 (Glaxo Group Ltd), WO04/056823 (Glaxo Group Ltd)and WO04/103998 (Glaxo Group Ltd) (e.g. Example 399 or 544 disclosedtherein). Further compounds are also disclosed in WO2005/058892,WO2005/090348, WO2005/090353, and WO2005/090354, all in the name ofGlaxo Group Limited.

Examples of anticholinergic agents are those compounds that act asantagonists at the muscarinic receptors, in particular those compoundswhich are antagonists of the M₁ or M₃ receptors, dual antagonists of theM₁/M₃ or M₂/M₃, receptors or pan-antagonists of the M₁/M₂/M₃ receptors.Exemplary compounds for administration via inhalation includeipratropium (for example, as the bromide, CAS 22254-24-6, sold under thename Atrovent), oxitropium (for example, as the bromide, CAS 30286-75-0)and tiotropium (for example, as the bromide, CAS 136310-93-5, sold underthe name Spiriva). Also of interest are revatropate (for example, as thehydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed inWO01/04118. Exemplary compounds for oral administration includepirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or CAS133099-07-7 for the hydrobromide sold under the name Enablex),oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline(CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS 124937-52-6 forthe tartrate, sold under the name Detrol), otilonium (for example, asthe bromide, CAS 26095-59-0, sold under the name Spasmomen), trospiumchloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, or CAS242478-38-2 for the succinate also known as YM-905 and sold under thename Vesicare).

Additional compounds are disclosed in WO 2005/037280, WO 2005/046586 andWO 2005/104745, incorporated herein by reference. The presentcombinations include, but are not limited to:

-   (3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    iodide;-   (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    bromide;-   4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide; and-   (1R,5S)-3-(2-cyano-2,2-diphenylethyl)-8-methyl-8-{2-[(phenylmethyl)oxy]ethyl}-8-azoniabicyclo[3.2.1]octane    bromide.

Other anticholinergic agents include compounds which are disclosed inU.S. patent application 60/487,981 including, for example:

-   (3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    bromide;-   (3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    bromide;-   (3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    4-methylbenzenesulfonate;-   (3-endo)-8,8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabicyclo[3.2.1]octane    bromide; and/or-   (3-endo)-8,8-dimethyl-3-[2-phenyl-2-(2-pyridinyl)ethenyl]-8-azoniabicyclo[3.2.1]octane    bromide.

Further anticholinergic agents include compounds which are disclosed inU.S. patent application 60/511,009 including, for example:

-   (endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitrile;    (endo)-8-methyl-3-(2,2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]octane;-   3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;-   3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionic    acid;-   (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide;-   3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propan-1-ol;-   N-benzyl-3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;-   (endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   1-benzyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;-   1-ethyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;-   N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-acetamide;-   N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzamide;-   3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-di-thiophen-2-yl-propionitrile;-   (endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzenesulfonamide;-   [3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;-   N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-methanesulfonamide;    and/or-   (endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide.

Further compounds include:

-   (endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide;-   (endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide; and/or    (endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide.

In one embodiment the invention provides a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereoftogether with an H1 antagonist. Examples of H1 antagonists include,without limitation, amelexanox, astemizole, azatadine, azelastine,acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine,chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine,carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene,ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine,ketotifen, loratadine, levocabastine, mizolastine, mequitazine,mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast,pyrilamine, promethazine, terfenadine, tripelennamine, temelastine,trimeprazine and triprolidine, particularly cetirizine, levocetirizine,efletirizine and fexofenadine. In a further embodiment the inventionprovides a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof together with an H3 antagonist(and/or inverse agonist). Examples of H3 antagonists include, forexample, those compounds disclosed in WO2004/035556 and inWO2006/045416. Other histamine receptor antagonists which may be used incombination with the compounds of the present invention includeantagonists (and/or inverse agonists) of the H4 receptor, for example,the compounds disclosed in Jablonowski et al., J. Med. Chem.46:3957-3960 (2003).

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with a PDE4 inhibitor.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with a β₂-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with a corticosteroid.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with a non-steroidal GR agonist.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with an anticholinergic.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with an antihistamine.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with a PDE4 inhibitor and a β₂-adrenoreceptoragonist.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with an anticholinergic and a PDE-4 inhibitor.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus pharmaceuticalcompositions comprising a combination as defined above together with apharmaceutically acceptable diluent or carrier represent a furtheraspect of the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. In one embodiment, the individual compounds will beadministered simultaneously in a combined pharmaceutical formulation.Appropriate doses of known therapeutic agents will readily beappreciated by those skilled in the art.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound of formula (I) or apharmaceutically acceptable salt thereof together with anothertherapeutically active agent.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound of formula (I) or apharmaceutically acceptable salt thereof together with a PDE4 inhibitor.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound of formula (I) or apharmaceutically acceptable salt thereof together with aβ₂-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound of formula (I) or apharmaceutically acceptable salt thereof together with a corticosteroid.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound of formula (I) or apharmaceutically acceptable salt thereof together with a non-steroidalGR agonist.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound of formula (I) or apharmaceutically acceptable salt thereof together with ananticholinergic.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound of formula (I) or apharmaceutically acceptable salt thereof together with an antihistamine.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound of formula (I) or apharmaceutically acceptable salt thereof together with a PDE4 inhibitorand a β₂-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a compound of formula (I) or apharmaceutically acceptable salt thereof together with ananticholinergic and a PDE4 inhibitor.

The invention will now be illustrated by way of the followingnon-limiting examples.

EXAMPLES

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thecompounds, compositions, and methods of the present invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention.

When the name of a commercial supplier is given after the name of acompound or a reagent, for instance “compound X (Aldrich)” or “compoundX/Aldrich”, this means that compound X is obtainable from a commercialsupplier, such as the commercial supplier named. If not referencedherein the compound or reagent can be purchased from a standard suppliersuch as Sigma Aldrich, Lancaster, Fluorochem, TCI etc.

The names of the Examples have been obtained using a compound namingprogramme which matches structure to name (e.g. ACD/Name Batch v 9.0).

General Experimental Details

Liquid Chromatography Mass Spectroscopy (LCMS) Methods

LCMS analysis has been carried out using one of the methods listedbelow.

Method A:

LCMS instrumentation consists of the following:

Column: Acquity UPLC BEH C₁₈ 1.7 μm 2.1 mm×50 mm. Column oven set to 40degrees

centigrade

Solvent A: Water 0.1% Formic Acid+10 mM Ammonium Acetate

Solvent B: MeCN: Water 95:5+0.05% Formic Acid

Injection volume: 0.5 μl

Injection technique: Partial loop overfill

UV detection: 220 to 330 nm

UV sampling rate: 40 points per second

MS scan range: 100 to 1000 amu

MS scanning rate: 0.2 second scan with a 0.1 second inter scan delay

MS scan function: Electrospray with pos neg switching

Cycle time: 2 minutes and 30 seconds

Gradient:

Flow Time ml/min % A % B 0 1 97 3 0.1 1 97 3 1.4 1 0 100 1.9 1 0 100 2 197 3

Method B:

The HPLC analysis was conducted on a Sunfire C18 column (30 mm×4.6 mmi.d. 3.5 μm packing diameter) at 30 degrees centigrade.

Solvent A=0.1% v/v solution of Formic Acid in Water.

Solvent B=0.1% v/v solution of Formic Acid in Acetonitrile.

The gradient employed was:

Time Flow Rate (min) (ml/min) % A % B 0 3 97 3 0.1 3 97 3 4.2 3 0 1004.8 3 0 100 4.9 3 97 3 5.0 3 97 3

The UV detection was an averaged signal from wavelength of 210 nm to 350nm and mass spectra were recorded on a mass spectrometer usingalternate-scan positive and negative mode electrospray ionization.

Method C:

The HPLC analysis was conducted on a Phenomenex Luma C18(2) (50 mm×2 mmi.d. 3 μm packing diameter, or validated equivalent) at 40 degreescentigrade.

Solvent A=0.05% v/v solution of TFA in Water.

Solvent B=0.05% v/v solution of TFA in Acetonitrile.

The gradient employed was:

Time Flow Rate (min) (ml/min) % A % B 0 1 100 0 8 1 5 95 8.01 1 100 0

The UV detection wavelength was analyte dependent and mass spectra wererecorded on a mass spectrometer using positive ion electrospray.

Method D:

The HPLC analysis was conducted on a Phenomenex Luma C18(2) (50 mm×2 mmi.d. 3 μm packing diameter, or validated equivalent) at 60 degreescentigrade.

Solvent A=0.05% v/v solution of TFA in Water.

Solvent B=0.05% v/v solution of TFA in Acetonitrile.

The gradient employed was:

Time Flow Rate (min) (ml/min) % A % B 0 1.5 100 0 2.5 1.5 5 95 2.7 1.5 595 2.9 1.5 100 0

The UV detection wavelength was analyte dependent and mass spectra wererecorded on a mass spectrometer using positive ion electrospray.

Mass Directed Automated Preparative HPLC Methods

The methods for the mass-directed automated preparative HPLC used forthe purification of compounds are described below:

Method A—High pH

Column Details:

Waters_XBRIDGE Prep C18 column 5 um OBD (30×150 mm)

The solvents employed were:

A=10 mM Ammonium Bicarbonate in water adjusted to pH 10 with aq. Ammoniasolution

B=Acetontrile+0.1% aq. Ammonia

Collection was triggered by uv, ms or a combination of the two. The UVdetection was an averaged signal from wavelength of 210 nm to 350 nm.Mass spectra were recorded on a mass spectrometer using analternate-scan positive and negative mode electrospray ionization.

Method B—Low pH

Column Details:

SUNFIRE C18 column (30×150 mm id 5 uM packing diameter)

The solvents employed were:

A=0.1% v/v solution of Formic Acid in Water.

B=0.1% v/v solution of Formic Acid in Acetontrile.

Collection was triggered by uv, ms or a combination of the two. The UVdetection was an averaged signal from wavelength of 210 nm to 350 nm.Mass spectra were recorded on a mass spectrometer using analternate-scan positive and negative mode electrospray ionization.

Method C

Column Details: XBRIDGE Shield RP18 column (100×19 mm, 5 uM packingdiameter

The solvents employed were:

A=10 mM Ammonium Bicarbonate in water adjusted to pH 10 with aq. Ammoniasolution

B=Methanol

Collection was triggered by uv, ms or a combination of the two. The UVdetection was an averaged signal from wavelength of 210 nm to 350 nm.Mass spectra were recorded on a mass spectrometer using analternate-scan positive and negative mode electrospray ionization.

INTERMEDIATES AND EXAMPLES Intermediate 16-Chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole

Method A

6-Chloro-4-iodo-1H-indazole (30 g, 108 mmol, available from Sinova) wasdissolved in N,N-dimethylformamide (300 ml) and cooled in an ice waterbath under nitrogen. Sodium hydride (5.17 g, 129 mmol) was addedportionwise, maintaining the temperature below 10° C. After fulladdition the reaction mixture was stirred for 20 mins thenbenzenesulfonyl chloride (16.5 ml, 129 mmol) was added dropwise over 15mins. The reaction was left to warm to RT overnight then poured onto icewater (2 L). The precipitated product was collected by filtration,washed with water (ca. 400 ml) and dried in a vacuum oven overnight togive the title compound (43.3 g).

LCMS (Method A): Rt 1.38 mins, MH⁺ 419.

Method B

To a stirred solution of 6-chloro-4-iodo-1H-indazole (633.6 g) in THF(5.7 L) was added sodium hydroxide (227.4 g) followed bytetra-n-butylammonium bisulphate (38.0 g) at 20±30° C., under a nitrogenatmosphere. The mixture was stirred at 20±30C for 1 h 3 min, thenbenzenesulphonyl chloride (319 ml) was added at such a rate as tomaintain the internal temperature at <25° C. Residual benzenesulphonylchloride was rinsed into the vessel with THF (630 mL), then the mixturestirred for 1 h 10 min. The mixture was cooled to <5° C. and water (12.7L) added at such a rate as to maintain internal temperature below 5±3°C., then the mixture stirred at 0-5° C. for 1 h 20 min. The solids werecollected by vacuum filtration, washed with water (2×1.9 L), sucked drythen further dried under vacuum with a nitrogen bleed at 40° C.±3° C.overnight to give the title compound (780.8 g).

LCMS (Method C): Rt 6.28 min, MH⁺ 419.

Intermediate 26-Chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole

6-Chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole (30 g, 71.7 mmol),tetrakis(triphenylphosphine)palladium(0) (8.1 g, 7.01 mmol), xylene (200ml), triethylamine (19.98 ml, 143 mmol) and hexamethylditin (21.8 ml,105 mmol) were heated at 150° C. for 2 h. The reaction mixture wasfiltered hot through Celite, washing with further xylene and the solventwas evaporated in vacuo. The residue was triturated with cyclohexane andthe precipitate collected by filtration and dried in a vacuum oven togive the title compound (14.4 g).

LCMS (Method A): Rt 1.51 mins, MH⁺ 457.

Intermediate 3a Ethyl2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate

In 4 batches, tetrakis(triphenylphosphine)palladium(0) (3.37 g, 2.92mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (6.65 g, 37.9 mmol,available from Apollo Scientific) and copper(I) iodide (1.11 g, 5.83mmol) were added to a solution of6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (13.28 g,29.2 mmol) in N,N-dimethylformamide (52 ml). In 3 of the batches,tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), ethyl2-chloro-1,3-oxazole-5-carboxylate (2.03 g, 11.59 mmol) and copper(I)iodide (0.34 g, 1.78 mmol) were added to a solution of6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (4.06 g,8.91 mmol) in N,N-dimethylformamide (16 ml). In the fourth batch,tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), ethyl2-chloro-1,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol) and copper(I)iodide (0.09 g, 0.48 mmol) were added to a solution of6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (1.10 g,2.42 mmol) in N,N-dimethylformamide (4 ml). Each batch was heated andstirred at 100° C. under microwave irradiation for 30 min. The mixtureswere allowed to cool to RT and the combined precipitated productsuspended in diethyl ether and collected by filtration, washing withfurther diethyl ether then drying in a vacuum oven for 72 h.Approximately 5.2 g of the resultant solid was dissolved indichloromethane and passed through Celite, eluting with furtherdichloromethane. The solvent was evaporated in vacuo to give the titlecompound as a pale orange solid (4.95 g).

LCMS (Method A): Rt 1.38 mins, MH⁺ 432.

Intermediate 3b Methyl2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate

To a stirred solution of 6-chloro-4-iodo-1-(phenylsulphonyl)-1H-indazole(549.8 g) in toluene (1.43 L) was added triethylamine (380 ml) at 20±3°C. under an atmosphere of nitrogen. Hexamethylditin (385 ml) in toluene(825 ml) was added, followed by toluene (275 ml) thentetrakis(triphenylphosphine) palladium (0) (154.7 g). The reactionmixture was heated to 120° C. and stirred at this temperature for 3 h.The mixture was allowed to cool to 20±3° C., filtered, then washed withtoluene (4.95 L). The filtrate was transferred to a clean vessel througha 5 μm Dominick hunter in-line filter, rinsing with further toluene (550ml). The batch was then washed with 50% aqueous KF solution (5.5 L), theaqueous slurry filtered and the filtrate recombined with the organicphase. The aqueous was separated and the organics washed successivelywith 50% aqueous KF (5.5 L), followed by water (5.5 L). The organiclayer was diluted with DMPU (2.75 L) then concentrated by vacuumdistillation to ca. 5.4 vols. To the resultant solution was added copper(I) iodide (25.5 g) followed by methyl2-chloro-1,3-oxazole-5-carboxylate (279 g, available from ApolloScientific) at 20±3° C. The solution was degassed via vacuum andnitrogen purges (×3). Tetrakis(triphenylphosphine) palladium (0) (78 g)was added, the mixture degassed (×3) and then heated to 85-900° C. for10 h. The mixture was diluted with DMSO (13.75 L) and cooled to 20±3°C., then water (2.75 L) added in ca. 1 vol portions over ca. 15 minsuntil crystallisation was initiated. The resultant suspension was agedat 20° C.±3° C. for 1.5 h. The solids were collected by vacuumfiltration, washed with water (2×2.75 L), sucked dry and then furtherdried in vacuo with a nitrogen bleed at 45° C.±5° C. overnight to givethe title compound (341.1 g).

LCMS (Method C): Rt 6.08 mins, MH⁺ 418

Intermediate 4{2-[6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol

Method A

A solution of ethyl2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate(5.11 g, 11.8 mmol) in dichloromethane (80 ml) was cooled to −25° C. inan oven dried round bottomed flask. Diisobutylaluminium hydride (25 ml,37.5 mmol, 1.5M solution in toluene) was added dropwise and the reactionstirred at −20° C. for 3 h. A 10% aqueous solution of potassium sodiumtartrate (80 ml) was added and the reaction mixture stirred for 5 min.The precipitated solid was filtered off and partitioned between ethylacetate (500 ml) and water (500 ml). The layers were separated and theaqueous washed with further ethyl acetate (3×150 ml). The combinedorganics were dried and evaporated in vacuo to give the title compoundas a yellow solid (1.1 g).

LCMS (Method A): Rt 1.09 mins, MH⁺ 390.

The remaining filtrate was largely concentrated in vacuo and the residuepartitioned between ethyl acetate (500 ml) and water (500 ml). Thelayers were separated and the aqueous extracted with further ethylacetate (3×150 ml). The combined organics were washed with water (2×150ml), dried over anhydrous sodium sulfate and evaporated to give thetitle compound as a yellow solid (1.9 g).

LCMS (Method A): Rt 1.09 mins, MH⁺ 390.

Method B

To a solution of ethyl2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate(1.15 g) in THF (17.25 ml), stirred under nitrogen in an ice bath wasadded a solution of diisobutylaluminium hydride (5.08 ml, 5.64 mmol) intoluene. The reaction mixture was stirred at 0° C. for 2 h. Sodiumsulphate decahydrate (2.5 g) was added, the mixture stirred at RT for 1h, then filtered, washed with THF (2×5 vols) and concentrated underreduced pressure to give the title compound (0.98 g).

LCMS (Method D): Rt 2.20 mins, MH⁺ 390.

Intermediate 54-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole

Method A

{2-[6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol(1.626 g, 4.17 mmol) was dissolved in anhydrous dichloromethane (20 ml)and carbon tetrabromide (2.77 g, 8.34 mmol) added. The reaction mixturewas cooled to 0° C. and a solution of triphenylphosphine (2.188 g, 8.34mmol) in dichloromethane (20 ml) added dropwise. After allowing to warmto RT and stirring for a further 3 h, the solvent was partially removedin vacuo and the solution purified directly by silica gelchromatography, eluting with 0-100% ethyl acetate in dichloromethane.The appropriate fractions were combined to give the title compound as acream solid (1.16 g).

LCMS (Method B): Rt 3.70 mins, MH⁺ 454.

Method B

Triphenylphosphine dibromide (20.60 g, 48.8 mmol) was added to asuspension of{2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol(9.06 g, 23.2 mmol) in dichloromethane (181 ml) at 0° C. The reactionmixture was stirred at 0° C. until completion. Water (91 ml) andsaturated sodium bicarbonate solution (91 ml) were added and the mixturestirred, then separated. The aqueous layer was extracted with furtherdichloromethane (45 ml) and the organics combined and washed with water(91 ml). The layers were separated and the organic concentrated todryness then redissolved in methanol (136 ml). After stirring for 30mins the resultant white suspension was filtered and the solid driedunder vacuum to give the title compound as an off-white solid (9.58 g).

LCMS (Method D): Rt 2.57 min, MH+ 452/454.

Intermediate 6a6-Chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole

4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole(0.580 g, 1.28 mmol) was dissolved in dichloromethane (5 ml) and (2R,6S)-2,6-dimethylmorpholine (0.317 ml, 2.56 mmol) added. The reactionmixture was stirred at RT for 3 h then the solvent removed under astream of nitrogen. The resultant yellow solid was dissolved indichloromethane (5 ml) and washed with water (2×2.5 ml). The layers wereseparated (hydrophobic frit) and the organic evaporated in vacuo to givethe title compound as a pale yellow solid (0.60 g).

LCMS (Method A): Rt 0.86 mins, MH⁺ 487.

¹H NMR (400 MHz, Chloroform-d) δ (ppm) 8.93 (d, J=1.0 Hz, 1H), 8.33 (dd,J=1.0, 1.5 Hz, 1H), 8.04-8.00 (m, 2H), 7.98 (d, J=1.5 Hz, 1H), 7.62 (tt,J=1.5, 7.5 Hz, 1H), 7.51 (t, J=7.5 Hz, 2H), 7.15 (s, 1H), 3.67 (s, 2H),3.75-3.66 (m, 2H), 2.79-2.72 (m, 2H), 1.86 (dd, J=10.5, 11.0 Hz, 2H),1.16 (d, J=6.5 Hz, 6H).

Similarly prepared using the appropriate amine was:

Intermediate LC/MS LC/MS Number Name Structure Amine R_(t) min MH⁺ 6b6-chloro-4-(5- {[4-(1- methylethyl)- 1- piperazinyl] methyl}-1,3-oxazol-2-yl)-1- (phenylsulfonyl)- 1H-indazole

1-(1- methylethyl) piperazine 0.77 500

Intermediate 72-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine

To 5-bromo-2-(methyloxy)-3-pyridinamine (18.93 g, 93 mmol, availablefrom Asymchem International) in a 1 L round-bottom flask was addednitrogen-purged 1,4-dioxane (500 ml) followed by4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (47.4 g, 186mmol), potassium acetate (27.5 g, 280 mmol) anddichloro{1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (7.61 g, 9.32 mmol). The mixture was then stirredat 80° C. under nitrogen for 2 h. The reaction mixture was allowed tocool then partitioned between ethyl acetate and water and filteredthrough a Celite pad. The aqueous layer was extracted further with ethylacetate (2×) and the combined organics washed with water, brine anddried over magnesium sulphate overnight. The mixture was filtered andthe filtrate concentrated in vacuo to give a dark brown solid. Theresidue was purified by silica gel chromatography, eluting in 0-50%ethyl acetate/dichloromethane. The appropriate fractions were combinedand evaporated to dryness and the residue triturated with cyclohexane.The resultant solid was filtered off and dried in vacuo to give thetitle compound as a light pink solid (11 μg).

LCMS (Method A) Rt 0.91 mins, MH⁺ 251.

Intermediate 8N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide

To a solution of2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine(0.5 g, 1.999 mmol) in pyridine (5 ml) was added methanesulphonylchloride (0.309 ml, 4.00 mmol) and the mixture stirred at 20° C. for 18hr then the solvent was removed in vacuo. The residue was partitionedbetween saturated sodium bicarbonate solution (10 ml) anddichloromethane (20 ml), separated by hydrophobic frit and purified bysilica gel chromatography, eluting with a gradient of dichloromethaneand methanol to give the title compound as a brown solid (0.46 g).

LCMS (Method A): Rt 0.98 mins, MH⁺ 329.

Intermediate 92,4-Difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide

To a stirred solution of2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine(3 g, 12.00 mmol) in pyridine (12 ml), 2,4-difluorobenzenesulfonylchloride (1.774 ml, 13.19 mmol) was added and the reaction mixturestirred at RT for 2 h. 2 N hydrogen chloride (aq) (20 ml) anddichloromethane (20 ml) were added and the layers separated. The aqueouslayer was washed with additional dichloromethane (2×15 ml) and theorganic layers combined, dried (hydrophobic frit) and evaporated invacuo to give a brown oil. There was still some pyridine in the reactionmixture so 2M hydrogen chloride (aq) and dichloromethane (15 ml) wereadded to extract one more time. The solvent was removed in vacuo to givethe title compound as an orange solid (4.3 g).

LCMS (Method A): Rt 1.20 min, MH⁺ 427 [NB. also observe Rt 0.73 min, MH⁺345 consistent with boronic acid (hydrolysis product due to HPLCeluent)].

Intermediate 10N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

To a solution of6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(0.2 g, 0.411 mmol) and2,4-difluoro-N-[2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide(0.228 mg, 0.534 mmol) in 1,4-dioxane (2 ml) was addedchloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021 mmol), potassiumphosphate tribasic (0.262 g, 1.23 mmol) and water (0.2 ml). The reactionmixture was heated to 120° C. with stirring for 3 h under microwaveirradiation, then filtered through a silica SPE, eulting with methanol.The solvent was removed and the residue partitioned betweendichloromethane (5 ml) and water (5 ml). The layers were separated andthe aqueous extracted with further dichloromethane (2×2.5 ml). Thecombined organics were concentrated under a stream of nitrogen and theresidue dissolved in DMSO and a few drops of dichloromethane (3 ml) andpurified by MDAP (method A) in 3 injections. The appropriate fractionswere evaporated in vacuo to give the title compound as a pale brownsolid (0.105 g).

LCMS (Method A): Rt 0.93 mins, MH⁺ 751.

Intermediate 112,4-Difluoro-N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide

To a solution of6-chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(0.2 g, 0.40 mmol) and2,4-difluoro-N-[2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide(0.222 g, 0.52 mmol) in 1,4-dioxane (2 ml) was addedchloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.2 g, 0.020 mmol), potassiumphosphate tribasic (0.255 g, 1.20 mmol) and water (0.2 ml). The reactionmixture was heated to 120° C. with stirring for 3 h under microwaveirradiation then filtered through a silica SPE, eluting with methanol.The solvent was removed in vacuo and the residue partitioned betweendichloromethane (5 ml) and water (5 ml). The layers were separated andthe aqueous extracted with further dichloromethane (2×2 ml). Thecombined organics were concentrated under a stream of nitrogen and theresidue purified using silica gel chromatography, eluting with 0-25%methanol in dichloromethane. The appropriate fractions were evaporatedin vacuo to give the title compound as a brown solid (0.081 g).

LCMS (Method A): Rt 0.85 mins, MH⁺ 764.

Intermediate 12 Ethyl2-[6-{1-[(1,1-dimethylethyl)(dimethyl)silyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate

To a solution of ethyl2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate(1.5 g, 3.47 mmol) in 1,4-dioxane (15 ml) and water (1.5 ml) was added{1-[(1,1-dimethylethyl)(dimethyl)silyl]-1H-indol-4-yl}boronic acid(1.243 g, 4.52 mmol, available from Combi-Blocks Inc.),chloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (0.097 g, 0.174 mmol) andpotassium phosphate tribasic (2.212 g, 10.42 mmol). The reaction mixturewas heated to 100° C. for 3 h, the solvent removed in vacuo and theresidue partitioned between dichloromethane (20 ml) and water (10 ml).Saturated sodium chloride solution (100 ml) was added and the organicphase separated and dried over anhydrous sodium sulphate. The crudeproduct was purified by silica gel chromatography, eluting with agradient of cyclohexane and ethyl acetate. The desired fractions wereconcentrated to give the title compound as a white solid (0.846 g),which by LCMS contained some unreacted starting material.

LCMS (Method A): Rt 1.71 mins, MH⁺ 627 (and Rt 1.39 min, MH⁺ 432consistent with ethyl2-[6-{1-[(1,1-dimethylethyl)(dimethyl)silyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate).

Intermediate 13{2-[6-{1-[(1,1-Dimethylethyl)(dimethyl)silyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol

To a solution of ethyl2-[6-{1-[(1,1-dimethylethyl)(dimethyl)silyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate(containing an impurity consistent with ethyl2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate)(0.84g) in dichloromethane (10 ml) at −20° C. was added diisobutylaluminiumhydride (2.68 ml, 2.68 mmol, 1M in hexanes). The reaction mixture wasstirred at −20° C. for 2 h then 10% ammonium chloride solution (10 ml)added. The mixture was stirred for 5 min then extracted withdichloromethane (10 ml), the layers separated (hydrophobic frit) and theorganic purified by silica gel chromatography, eluting with a gradientof cyclohexane and ethyl acetate. The desired fractions wereconcentrated to give the title compound as a pale yellow solid (0.36 g),which by LCMS contained an impurity consistent with2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol.LCMS (Method A): Rt 1.55 mins, MH⁺ 585 (and Rt 1.11 mins, MH⁺ 390consistent with{2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanolimpurity).

Intermediate 146-Chloro-4-(5-{[(2R,6R)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole

To a solution of4-[5-(bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole(750 mg, 1.657 mmol) in dichloromethane (50 mL) stirred in air at roomtemp, was added neat 2,6-dimethylmorpholine (191 mg, 1.657 mmol,available from Aldrich as a mixture of isomers). The reaction mixturewas stirred at 20° C. for 20 hr. Volatiles were removed using a rotaryevaporator then the crude material was pre-absorbed onto Fluorosil™ andpurified by column chromatography on silica (100 g) using a 0-100% ethylacetate-cyclohexane gradient over 60 mins. Two diastereoisomers wereisolated. Appropriate fractions were combined and evaporated in vacuo togive the title compound as a yellow oil (226 mg).

¹H NMR confirmed the structure as the trans isomer. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.92 (d, J=1.0 Hz, 1H), 8.32 (dd, J=1.0, 1.5 Hz,1H), 8.04-8.00 (m, 2H), 7.97 (d, J=1.5 Hz, 1H), 7.62 (tt, J=1.5, 7.5 Hz,1H), 7.54-7.48 (m, 2H), 7.13 (s, 1H), 4.08-3.99 (m, J=3.5, 6.0, 6.5,6.5, 6.5 Hz, 2H), 3.66 (d, J=14.5 Hz, 1H), 3.61 (d, J=14.5 Hz, 1H), 2.56(dd, J=3.0, 10.5 Hz, 2H), 2.23 (dd, J=6.0, 10.5 Hz, 2H), 1.24 (d, J=6.5Hz, 6H).

Intermediate 15 1,1-Dimethylethyl4-({2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methyl)-1-piperazinecarboxylate

1,1-Dimethylethyl 1-piperazinecarboxylate (185 mg, 0.994 mmol) wasdissolved in 1 ml of DCM and triethylamine (0.185 mL, 1.325 mmol) wasadded dropwise. The mixture was stirred for 1 h, then concentrated invacuo to afford a yellow solid. This was dissolved in water/DCM (1:1, 50ml) and the organic phase was collected then concentrated in vacuo toafford the title compound as a yellow gum (347 mg).

LCMS (Method A) Rt 1.16 min (poor ionisation, (M+MeCN)⁺ 599 observed).

Example 1N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide

Method A

To a solution of6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(0.20 g, 0.411 mmol) andN-[2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methanesulfonamide(0.175 g, 0.534 mmol) in 1,4-dioxane (2 ml) was addedchloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021 mmol), potassiumphosphate tribasic (0.262 g, 1.23 mmol) and water (0.2 ml). The reactionmixture was heated and stirred at 120° C. under microwave irradiationfor 1 h.

Additionalchloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane(11.5 mg, 0.021 mmol) and potassium phosphate tribasic (80 mg) wereadded and the reaction heated to 120° C. under microwave irradiation for1 h. Additional potassium phospate tribasic (80 mg) was added and thereaction heated under the same conditions for a further 1 h. Thereaction mixture was filtered through a silica SPE and eluted withmethanol. The solvent was removed in vacuo and the residue partitionedbetween dichloromethane (5 ml) and water (5 ml). The layers wereseparated and the aqueous extracted with further dichloromethane (2×2ml). The combined organics were concentrated under a stream of nitrogenand the residue dissolved in MeOH:DMSO (3 ml, 1:1, v/v) and purified byMDAP (method A) in 3 injections. The appropriate fractions were combinedand concentrated to give a white solid which was dissolved in MeOH:DMSO(1 ml, 1:1, v/v) and further purified by MDAP (method B). Theappropriate fractions were basified to pH 6 with saturated sodiumbicarbonate solution and extracted with ethyl acetate (2×25 ml). Thecombined organics were dried and evaporated in vacuo to give a whitesolid which was further dried under nitrogen at 40° C. for 3 h to givethe title compound as a white solid (26 mg).

LCMS (Method A): Rt 0.53 mins, MH⁺ 513.

Method B

N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide(101 g, 308 mmol),6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(83.3 g, 154 mmol) and sodium bicarbonate (38.8 g, 462 mmol) weresuspended in 1,4-dioxane (1840 ml) and water (460 ml) under nitrogen andheated to 80° C. Chloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (8.63 g, 15.40 mmol) was addedand the mixture stirred overnight at 80° C.

The reaction mixture was cooled to 45° C., sodium hydroxide 2M aq. (770ml, 1540 mmol) added and the reaction heated to 45° C. for 4 hours. Themixture was cooled to RT and diluted with water (610 mL).Dichloromethane (920 mL) was added, and the mixture was filtered twicethrough Celite (washed with 200 mL 1,4-dioxane/DCM 2:1 each time). Thephases were separated, and aqueous washed with 1,4-dioxane/DCM 2:1 (500mL). The aqueous phase was neutralised with hydrochloric acid to pH ˜7and extracted with 1,4-dioxane/DCM 2:1 (1 L), then 1,4 dioxane/DCM 1:1(2×500 mL). The organics were washed with brine (500 mL), and filteredthrough Celite (washed with 200 mL 1,4 dioxane/DCM 2:1), and evaporatedto yield a dark black solid, which was purified in 4 batches:

Batch 1: 28 g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 mL)and purified by column chromatography (1.5 kg silica column), elutingwith Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as anoff-white solid (14.78 g).

Batch 2: 30 g was dissolved in methanol and mixed with Fluorisil. Thesolvent was then removed by evaporation and the solid purified by columnchromatography (1.5 kg silica column, solid sample injection module),eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compoundas an off-white solid (9.44 g).

Batch 3: 31 g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 mL)and purified by column chromatography (1.5 kg silica column), elutingwith Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as anoff-white solid (17 g).

Batch 4: 29 g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 mL)and purified by column chromatography (1.5 kg silica column), elutingwith Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as anoff-white solid (21 g).

The mixed fractions from the 4 columns were combined and evaporated toyield 19 g which was dissolved in 200 mL of Toluene/Ethanol/Ammonia80:20:2 (+ additional 4 ml of 0.88 NH3 to help solubility) then purifiedby column chromatography (1.5 kg silica column), eluting withToluene/Ethanol/Ammonia 80:20:2 to give the title compound as anoff-white solid (6.1 g).

All pure batches were combined (68 g) and recrystallised from ethanol(1200 mL). The suspension was heated to reflux and a solution formed.The resulting solution was then cooled to room temperature overnight.The resulting solid was then collected by filtration, washed sparinglywith ethanol and dried under vacuum to give the title compound as anoff-white solid (56 g). This material was recrystallised again fromethanol (1100 mL). The suspension was heated to reflux and a solutionformed. The resulting solution was then cooled to room temperatureovernight with stirring. The resulting solid was collected by filtrationand washed sparingly with ethanol. The solid was dried in vacuo at 60°C. for 5 hrs to give the title compound as an off-white solid (45.51 g).

LCMS (Method A): Rt 0.61 mins, MH⁺ 513.

The filtrate from the two recrystallisations was evaporated to yield ˜23g of a solid residue that was dissolved in 200 mL ofToluene/Ethanol/Ammonia 80:20:2 (+ additional 4 ml of 0.88 NH3 to helpsolubility) then purified by column chromatography (1.5 kg silicacolumn), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give a furthercrop of the title compound as an off-white solid (18.5 g). This solidwas then recrystallised from ethanol (370 mL). The suspension was heatedto reflux then the resulting solution stirred for 20 mins before beingallowed to cool to room temperature naturally overnight. The solid wasthen dried in vacuo at 65° C. overnight to give the title compound as anoff-white solid (11.90 g).

LCMS (Method A): Rt 0.62 mins, MH⁺ 513.

Example 2N-[5-[4-(5-{[4-(1-Methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide

To a solution of6-chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(200 mg, 0.400 mmol) andN-[2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methanesulfonamide(171 mg, 0.520 mmol) in 1,4-dioxane (2 ml) was addedchloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.2 mg, 0.020 mmol), potassiumphosphate tribasic (255 mg, 1.20 mmol) and water (0.2 ml). The reactionmixture was heated and stirred at 120° C. under microwave irradiationfor 3 h. The reaction mixture was filtered through a silica SPE andeluted with methanol. The solvent was removed in vacuo and the residuepartitioned between dichloromethane (5 ml) and water (5 ml). The layerswere separated and the aqueous extracted with further dichloromethane(2×2 ml). The combined organics were concentrated under a stream ofnitrogen and the residue dissolved in MeOH:DMSO (2 ml, 1:1, v/v) andpurified by MDAP (method A) in 2 injections. The appropriate fractionswere combined and concentrated and the residue dissolved in MeOH:DMSO (1ml, 1:1, v/v) and further purified by MDAP (method B). The appropriatefractions were basified to pH 7 with saturated sodium bicarbonatesolution and extracted with dichloromethane (2×20 ml). The combinedorganics were dried (hydrophobic frit) and concentrated to give thetitle compound as a white solid (22 mg).

LCMS (Method A): Rt 0.51 mins, MH⁺ 526.

Example 3N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide(105 mg, 0.140 mmol) was suspended in isopropanol (2 ml) and 2M sodiumhydroxide (aq) (0.699 ml, 1.399 mmol) added. The reaction mixture wasstirred at RT for 2 h, the solvent removed under a stream of nitrogenand the residue dissolved in water (1 ml) and acidified to pH-6 by theaddition of 2M hydrogen chloride (aq)(a black precipitate formed). Thesuspension was extracted with dichloromethane (3×2 ml) and the combinedorganics dried to give a brown solid. This was combined with the blackprecipitate which remained insoluble in the extraction, dissolved inMeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method A). Theappropriate fractions were concentrated in vacuo to give the titlecompound as a white solid (20 mg).

LCMS (Method A): Rt 0.69 mins, MH⁺ 611.

Example 42,4-Difluoro-N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide

2,4-Difluoro-N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide(81 mg, 0.106 mmol) was suspended in isopropanol (2 ml) and 2M sodiumhydroxide (aq) (0.53 ml, 1.060 mmol) was added. The reaction mixture wasstirred at RT for 2 h, the solvent removed and the residue dissolved inwater (1 ml) and acidified to pH-6 by the addition of 2M hydrogenchloride (aq). The resultant suspension was extracted withdichloromethane (3×2 ml), the organic layer separated (hydrophobic frit)and concentrated in vacuo to give a brown solid which dissolved inMeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method A). Theappropriate fractions were concentrated in vacuo to give the titlecompound as a white solid (45 mg).

LCMS (Method A): Rt 0.65 mins, MH⁺ 624.

Example 54-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-6-(1H-indol-4-yl)-1H-indazole

To a solution of6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(50 mg, 0.103 mmol) in 1,4-dioxane (1.5 ml) and water (0.15 ml) wasadded {1-[1,1,-dimethylethyl)(dimethl)silyl]1-Hindol-4-yl}boronic acid(37 mg, 0.133 mmol),chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane(5.75 mg, 10.27 μmol) and potassium phosphate tribasic (65 mg, 0.308mmol). The reaction mixture was heated under microwave irradiation at100° C. for 40 min. The solvent was removed and the residue dissolved in10% methanol in dichloromethane (2 ml) and purified by silica gelchromatography, eluting with a gradient of cyclohexane and ethylacetate. The appropriate fractions were concentrated to give a brown gumwhich was treated directly with tetra-n-butylammonium fluoride (0.2 ml,0.2 mmol, 1M in tetrahydrofuran) and allowed to stand at 20° C. for 18h. The solvent was removed and the residue dissolved in 1,4-dioxane (1ml) and treated with 2M sodium hydroxide (1 ml) and allowed to stand at20° C. for 48 h. The solvent was removed and the residue triturated with10% methanol in dichloromethane then purified by silica gelchromatography, eluting with a gradient of dichloromethane and methanolto give a pale brown solid which was further purified by SCX SPE (1 g),eluting with 0.5M ammonia in 1,4-dioxane. The solvent was removed andthe residue further purified by MDAP to give the title compound as awhite solid (14 mg). LCMS (Method A): Rt 0.70 mins, MH⁺ 428.

Example 66-(1H-Indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole

Method A

6-Chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(97 mg, 0.194 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (61.3 mg,0.252 mmol, available from Frontier Scientific Europe),chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (10.87 mg, 0.019 mmol) andpotassium phosphate tribasic (124 mg, 0.582 mmol) were dissolved in1,4-dioxane (1 ml) and water (0.1 ml) and heated in a Biotage Initiatormicrowave at 100° C. for 30 min. Additional4-(4,4,5,5-tetramethyl-1,3,2-dioxabotolan-2-yl)-1H-indole (61.3 mg,0.252 mmol) andchloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (5 mg) were added and thereaction heated at 110° C. for 30 min, then 140° C. for 30 min. Thesolvent was removed in vacuo and the residue purified by silica gelchromatography, eluting with 0-25% methanol in dichloromethane. Theappropriate fractions were combined and concentrated to give a brownsolid which was dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified byMDAP (method A). The appropriate fractions were concentrated in vacuo togive the title compound as a white solid (30 mg).

LCMS (Method A): Rt 0.57 mins, MH⁺ 441.

Method B

6-Chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(75.17 g, 150 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (73.1 g, 301mmol), sodium bicarbonate (37.9 g, 451 mmol), andchloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (8.43 g, 15.03 mmol) weresuspended in nitrogen purged 1,4-dioxane (1200 mL) and water (300 mL).The reaction vessel was placed under alternating vacuum and nitrogenfive times with overhead stirring, then finally placed under a nitrogenatmosphere and heated to 120° C. for 2.5 h.

The reaction mixture was cooled to 45° C. and then treated with 2Maqueous sodium hydroxide (376 mL, 752 mmol). After stirring at 45° C.overnight (˜13 h), the mixture was cooled to RT and DCM (600 ml) andwater (400 ml) were added. The layers were separated and the aqueousre-extracted with DCM:1,4-dioxane (1:1). Brine was added and the mixturefiltered through Celite, washing with DCM:1,4-dioxane (1:1). The layerswere separated and 2M HCl (1000 ml) added to the organic. The mixturewas again filtered through Celite washing with 500 ml 2M HCl keeping thewashings separate. The filtrate layers were then separated and theorganic layer was washed with the acid washings from the Celite. Layerswere separated and the acidic aqueous combined. This was thenback-washed with 2×500 ml of DCM; each wash requiring a Celitefiltration. The acidic aqueous was then given a final filtration throughCelite washing the Celite pad with 150 ml of 2M HCl.

The acidic aqueous was transfered to a beaker (5000 ml) and withvigorous stirring 2M NaOH was added to basify the mixture to pH 10-11.The mixture was then extracted using 1,4-dioxane:DCM (1:1) (5×500 ml).The combined organics were washed with brine, dried over magnesiumsulphate, filtered and evaporated to yield a brown foam that was driedin vacuo at 50° C. overnight.

This material was split into three batches and each was purified byreverse phase column chromatography (3×1.9 kg C18 column), loading inDMF/TFA (1:1, 30 ml) then eluting with 3-40% MeCN in Water+0.25% TFA(Note: Columns 2 & 3 used a different gradient starting with 10% MeCN).

Appropriate fractions were combined, the acetotnitrile removed in vacuoand the acidic aqueous basified to pH10 by addition of saturated aqueoussodium carbonate solution to the stirred solution. The resultant solidwas collected by filtration, washed with water then dried in vacuo at65° C. overnight to give the title compound (28.82 g) as a pale brownfoam.

LCMS (Method A): Rt 0.68 mins, MH⁺ 441.

¹H NMR (400 MHz, DMSO-d₆) d=13.41 (br. s., 1H), 11.35 (br. s., 1H), 8.59(br. s., 1H), 8.07 (d, J=1.5 Hz, 1H), 7.90 (br. s., 1H), 7.51-7.44 (m,2H), 7.32 (s, 1H), 7.27-7.21 (m, 2H), 6.61-6.58 (m, 1H), 3.73 (br. s.,2H), 2.64-2.36 (m, 9H), 0.97-0.90 (m, 6H)

Example 76-(1H-Indol-4-yl)-4-[5-(4-morpholinylmethyl)-1,3-oxazol-2-yl]-1H-indazoletrifluoroacetate

To a solution of{2-[6-{1-[(1,1-dimethylethyl)(dimethyl)silyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol(containing an impurity consistent with2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol)(350 mg) in dichloromethane (10 ml) was added carbon tetrabromide (397mg, 1.197 mmol). The reaction mixture was cooled to 0° C. andtriphenylphosphine (314 mg, 1.197 mmol) as a solution in dichloromethane(2 ml) was added dropwise. The reaction mixture was allowed to warm toRT then the solvent partially removed and the solution purified directlyby silica gel chromatography, eluting with a gradient of dichloromethaneand ethyl acetate. The desired fractions were concentrated to give abrown solid (37 mg).

To a solution of the solid (30 mg, 0.056 mmol) in dichloromethane (5 ml)was added morpholine (9.8 mg, 0.112 mmol) and the mixture stirred at 20°C. for 18 h. The solvent was removed and the residue dissolved in1,4-dioxane (2 ml) and 2M sodium hydroxide solution (1 ml, 2.0 mmol)added. The reaction mixture was stirred at 20° C. for 18 h then thesolvent removed and the residue triturated with 10% methanol indichloromethane (1 ml) and purified by silica gel chromatography,eulting with a gradient of dichloromethane and dichloromethane+1%ammonia in methanol. The desired fractions were concentrated andpurified by MDAP to give the title compound as a brown solid (3 mg).LCMS (Method A): Rt 0.65 mins, MH⁺ 400.

Example 8N-[5-[4-(5-{[(2R,6R)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide

To a solution of6-chloro-4-(5-{[(2R,6R)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(109.5 mg, 0.225 mmol),N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide(148 mg, 0.450 mmol) and sodium bicarbonate (56.7 mg, 0.675 mmol) in1,4-Dioxane (5 mL) and Water (1.5 mL) stirred in air at room temp wasadded solid Solvias Catalyst (12.60 mg, 0.022 mmol). The reactionmixture was stirred at 120° C. for 2 hr. After this time, sodiumhydroxide solution (2N, 0.5 mL) was added and the reaction mixture leftto stir at room temperature for two hours. On cooling, the reactionmixture was passed through a celite cartridge (10 g) and washed withethyl acetate. The resulting solution was evaporated and the cruderesidue purified by MDAP (Method C). Appropriate fractions were combinedand concentrated in vacuo to afford the title compound (43 mg).

LCMS (Method A) Rt 0.63 mins, MH⁺ 513.

Example 96-(1H-Indol-4-yl)-4-[5-(1-piperazinylmethyl)-1,3-oxazol-2-yl]-1H-indazole

1,1-Dimethylethyl4-({2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methyl)-1-piperazinecarboxylate(303 mg, 0.543 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (172 mg, 0.706mmol, available from Frontier Scientific),chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (30 mg, 0.054 mmol,available from Fluka) and tripotassium phosphate (346 mg, 1.629 mmol)were dissolved in 1,4-Dioxane (10 mL) and Water (2.5 mL). The reactionvessel was sealed and heated in Biotage Initiator microwave at 150° C.for 30 min. Aqueous 2M NaOH (5 ml) was then added and the mixturestirred for 2 hours. An additional portion of aqueous 2M NaOH (3 ml) wasadded and stirring continued until deprotection appeared complete byLCMS analysis. DCM was then added and the mixture was passed through aphase separator. The organic phase was collected.

The aqueous phase was back extracted with DCM then the organic phaseswere combined and evaporated to give a brown oil. This was dissolved in5 ml of 4M HCl in 1,4 dioxane and left stirring. The mixture wasconcentrated in vacuo and the resultant solid partitioned between DCMand 2M acqueous HCl. The aqueous phase was basified with 2M aquous NaOH,then washed with DCM. The organic phase was concentrated in vacuo, thenthe residue dissolved in 2 ml DMSO/MeOH (1:1) and purified by MDAP(Method A). Combining appropriate fractions and concentrating by blowdown under nitrogen at 40° C., afforded the title compound (43 mg).

LCMS (Method A) Rt 0.62 mins, MH⁺ 399.

Example 106-(1H-Indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolehydrochloride

A solution of6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazolein tetrahydrofuran (THF) (7.5 mL) was heated to 60° C. under nitrogen.2M hydrochloric acid in diethyl ether (0.567 mL, 1.135 mmol) andtetrahydrofuran (THF) (0.5 mL) were mixed and added via a droppingfunnel. The solution was stirred at 60° C. for 30 mins before beingslowly cooled to RT. After stirring at RT for a further 30 mins thesolid was filtered off, then recombined with the liquors and evaporatedto dryness. THF (10 mL) was added and the slurry was cycled from RT toreflux 3 times (30 mins hold at higher/low temp). The slurry was stirredat RT for one hour then filtered under vacuum and the resultant soliddried in a vacuum oven at 50° C. overnight to give the title compound asa an off-white solid (322 mg).

LCMS (Method A): Rt 0.66 mins, MH⁺ 441. ¹H NMR (400 MHz, DMSO-d₆)d=13.53 (s, 1H), 11.44 (br. s., 1H), 10.20 (br. s., 1H), 8.61 (s, 1H),8.08 (s, 1H), 7.92 (s, 1H), 7.52-7.46 (m, 2H), 7.41 (s, 1H), 7.28-7.19(m, 2H), 6.60 (br. s., 1H), 3.87 (s, 2H), 3.41-3.32 (m, 3H+, obscured byH2O), 3.10-2.93 (m, 4H), 2.71-2.58 (m, 2H), 1.23 (d, J=6.5 Hz, 6H).

Example 116-(1H-Indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazoledihydrochloride

6-(1H-Indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole(19.4 mg, 0.044 mmol) was dissolved in tetrahydrofuran (THF) (0.5 ml)and 4M HCl in dioxane (0.022 ml, 0.088 mmol) added. The mixture wasstirred at RT for 2 h, then the cream precipitate formed was filteredoff and dried in a vacuum oven overnight to give the title compound as abeige solid (15.5 mg).

LCMS (Method A): Rt 0.65 mins, MH⁺ 441.

¹H NMR (600 MHz, DMSO-d₆) d=13.47 (br. s., 1H), 11.38 (br. s., 1H),10.17 (br. s., 1H), 8.66 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.51 (br.s., 1H), 7.49 (dt, J=1.0, 7.5 Hz, 1H), 7.47 (t, J=3.0 Hz, 1H), 7.25 (t,J=7.0 Hz, 1H), 7.23 (dd, J=1.5, 7.0 Hz, 1H), 6.60 (ddd, J=1.0, 2.0, 3.0Hz, 1H), 4.17 (br. s., 2H), 3.50-3.39 (m, 3H), 3.35-3.25 (m, 2H),3.22-3.11 (m, 2H), 2.99-2.76 (m, 2H), 1.24 (d, J=6.5 Hz, 6H).

Example 12N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(R)-mandelate

Method A

N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(113 mg, 0.220 mmol) was suspended in water (18 ml) and (R)-mandelicacid (0.33M solution in water, 735 μl, 0.242 mmol) was added. Themixture was stirred at RT overnight then concentrated and dried in avacuum oven at 50° C. overnight to give the title compound as a whitesolid (133 mg).

LCMS (Method A): Rt 0.60 mins, MH⁺ 513.

¹H NMR (400 MHz, DMSO-d₆) d=13.53 (br. s., 1H), 9.43 (s, 1H), 8.58 (s,1H), 8.43 (d, J=2.5 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.93 (d, J=1.5 Hz,1H), 7.89 (s, 1H), 7.36 (s, 1H), 7.43-7.24 (m, 5H), 5.01 (s, 1H), 3.99(s, 3H), 3.75 (s, 2H), 3.63-3.52 (m, 2H), 3.11 (s, 3H), 2.81 (d, J=10.5Hz, 2H), 1.78 (t, J=10.5 Hz, 2H), 1.04 (d, J=6.5 Hz, 6H).

Note—mandelate only present at a molar ratio of 0.8.

Method B

N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(3.17 mg) was suspended in 5% dextrose/water (3 ml). A 100 mg/ml aqueoussolution of (R)-mandelic acid (10 μl) was added and the mixture stirredfor 45 min to give the title compound as a clear solution.

Polymorph Experimental Example 10

X-Ray Powder Diffraction (XRPD)

The data were acquired on a PANalytical X'Pert Pro powderdiffractometer, model PW3040/60, serial number DY1850 using anX'Celerator detector. The acquisition conditions were: radiation: Cu Kα,generator tension: 40 kV, generator current: 45 mA, start angle: 2.0°2θ□, end angle: 40.0 °□2θ, step size: 0.0167 °2θ, time per step: 31.75seconds. The sample was prepared by mounting a few milligrams of sampleon a Si wafer (zero background) plates, resulting in a thin layer ofpowder.

The X-ray powder diffraction (XRPD) data are shown in FIG. 1.

Characteristic peaks for the solid state form are summarised in Table 1with calculated lattice spacings. Peak positions were measured usingHighscore software.

TABLE 1 2θ/° d-spacing/Å 5.2 17.0 10.3 8.6 12.8 6.9 14.8 6.0 15.1 5.915.6 5.7 16.8 5.3 17.2 5.2 18.3 4.9 19.6 4.5 20.9 4.2 21.3 4.2 21.7 4.123.2 3.8 24.0 3.7 24.9 3.6 26.0 3.4 27.1 3.3 27.5 3.2 28.2 3.2 28.5 3.1

Example 1

X-Ray Powder Diffraction (XRPD)

The data were acquired using a similar method to that described above.

The X-ray powder diffraction (XRPD) data are shown in FIG. 2.

Characteristic peaks for the solid state form are summarised in Table 2with calculated lattice spacings. Peak positions were measured usingHighscore software.

TABLE 2 2θ/° d-spacing/Å 4.5 19.8 6.3 13.9 7.8 11.3 8.8 10.1 9.9 8.910.4 8.5 10.7 8.3 11.3 7.8 11.7 7.5 12.2 7.3 12.9 6.9 14.0 6.3 14.5 6.115.2 5.8 15.4 5.7 16.1 5.5 16.5 5.4 16.8 5.3 17.7 5.0 17.9 5.0 18.5 4.819.0 4.7 20.7 4.3 21.4 4.1 22.4 4.0 22.6 3.9 23.4 3.8 23.7 3.8 24.9 3.625.4 3.5 25.7 3.5

Biological Data

PI3K Alpha, Beta, Delta and Gamma Assays

Assay Principle

The assay readout exploits the specific and high affinity binding ofPIP3 to an isolated pleckstrin homology (PH) domain in the generation ofa signal. Briefly, the PIP3 product is detected by displacement ofbiotinylated PIP3 from an energy transfer complex consisting of Europium(Eu)-labelled anti-GST monoclonal antibody, a GST-tagged PH domain,biotin-PIP3 and Streptavidin-APC. Excitation of Eu leads to a transferof energy to APC and a sensitized fluorescence emission at 665 nm. PIP3formed by PI3kinase activity competes for the binding site on the PHdomain, resulting in a loss of energy transfer and a decrease in signal.

Assay Protocol

Solid compounds are typically plated with 0.1 μl of 100% DMSO in allwells (except column 6 and 18) of a 384-well, v bottom, low volumeGreiner plate. The compounds are serially diluted (4-fold in 100% DMSO)across the plate from column 1 to column 12 and column 13 to column 24and leave column 6 and 18 containing only DMSO to yield 11concentrations for each test compound.

The assays are run using specific PI3 kinase kits from Millipore(Cat#33-001)

The assay kit consist of the following:

-   -   4×PI3K reaction buffer (Contains 200 mM Hepes pH 7, 600 mM NaCl,        40 mM Mgcl₂, <1% Cholate (w/v), <1% Chaps (w/v), 0.05% Sodium        Azide (w/v))    -   PIP2 (1 mM)    -   3×Biotin PIP3 (50 μM)    -   Detection Mix C (Contains 267 mM KF)    -   Detection Mix A (Contains 60 μg/ml streptavadin-APC)    -   Detection Mix B (Contains 36 μg/ml Europium-anti-GST(Anti-GST-K)        and 90 μg/ml GST-GRP1-PH-Domain and 1 mM DTT)    -   Stop Solution (Contains 150 mM EDTA)

Manually add 3 μl of Reaction buffer (contains 1 mM DTT) to column 18only for 100% inhibition control (no activity)

Manually add 3 μl of 2× Enzyme solution to all wells except column 18.Preincubate with compound for 15 minutes.

Manually add 3 μl of 2× Substrate solution to all wells. (column 6represents 0% inhibition control)

Leave plate for 1 hr (cover from light) (In the case of Gamma only a 50min incubation is required)

Manually add 3 μl Stop/Detection solution to all wells

Leave plate for 1 hour (cover from light)

The assay is read upon the BMG Rubystar and the ratio data is utilisedto calculate 11 point curves.

NB The substrate solution (concentrations) differ with each isoform (seebelow)

Alpha

2× substrate solution containing 500 μM ATP, 16 μM PIP2 and 0.030 μM 3×biotin-PIP3.

Beta

2× substrate solution containing 800 μM ATP, 16 μM PIP2 and 0.030 μM 3×biotin-PIP3.

Delta

2× substrate solution containing 160 μM ATP, 10 μM PIP2 and 0.030 μM 3×biotin-PIP3.

Gamma

2× substrate solution containing 30 μM ATP, 16 μM PIP2 and 0.030 μM 3×biotin-PIP3.

Analysis Method

Data processed through the XC50 4-parameter logistic curve fit algorithmin Activity Base.

Normalise to % inhibition between the high and low controls (0% and 100%inhibition respectively)

Primary Module fit: Slope, Min and Max asymptotes varies

Secondary Module fits: (1) Fix Min asymptote, (2) Fix Max asymptote, (3)Fix Min and Max asymptotes

Curve Fit QC: pXC50 95% CL ratio >10

−20<Min asymptote <20

80<Max asymptote <120

The compounds and salts of Examples 1 to 10 and 12 were tested in thePI3K Alpha, Beta, Delta and/or Gamma assays above or similar assays andwere found to have a mean pIC₅₀ in the PI3K Delta assay of at least 7 orgreater.

The compounds and salts of at least Examples 1, 2, 5 to 10 and 12 werefound to have at least tenfold selectivity for PI3K Delta over PI3KAlpha, Beta and/or Gamma.

1-12. (canceled)
 13. A compound of formula (I):

wherein R¹ is 9- or 10-membered bicyclic heteroaryl wherein the 9- or10-membered bicyclic heteroaryl contains from one to three heteroatomsindependently selected from oxygen and nitrogen and is optionallysubstituted by C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, —CN or —NHSO₂R⁵, orpyridinyl optionally substituted by one or two substituentsindependently selected from C₁₋₆alkyl, —OR⁶, halo and —NHSO₂R⁷; R² andR³, together with the nitrogen atom to which they are attached, arelinked to form a 6- or 7-membered heterocyclyl wherein the 6- or7-membered heterocyclyl optionally contains an oxygen atom or a furthernitrogen atom; R⁴ is hydrogen or methyl; R⁶ is hydrogen or C₁₋₄alkyl;and R⁵ and R⁷ are each independently C₁₋₆alkyl, or phenyl optionallysubstituted by one or two substituents independently selected from halo;or a salt thereof.
 14. The compound according to claim 13, wherein R¹ is9-membered bicyclic heteroaryl wherein the 9-membered bicyclicheteroaryl contains one or two nitrogen atoms, or pyridinyl optionallysubstituted by one or two substituents independently selected from —OR⁶and —NHSO₂R⁷.
 15. A compound according to claim 13, wherein R¹ isindolyl.
 16. A compound according to claim 13, wherein R¹ is pyridinyloptionally substituted by one or two substituents independently selectedfrom —OR⁶ and —NHSO₂R⁷.
 17. A compound according to claim 13, wherein R²and R³, together with the nitrogen atom to which they are attached, arelinked to form a 6-membered heterocyclyl wherein the 6-memberedheterocyclyl optionally contains an oxygen atom or a further nitrogenatom.
 18. A compound according to claim 13, wherein R² and R³, togetherwith the nitrogen atom to which they are attached, are linked to form a6-membered heterocyclyl wherein the 6-membered heterocyclyl contains anoxygen atom.
 19. A compound according to claim 13, wherein R² and R³,together with the nitrogen atom to which they are attached, are linkedto form a 6-membered heterocyclyl wherein the 6-membered heterocyclylcontains a further nitrogen atom.
 20. A compound according to claim 13,wherein R⁴ is hydrogen.
 21. A compound according to claim 13 wherein thecompound of formula (I) is in the form of a pharmaceutically acceptablesalt thereof.